Stem Cells http://www.stemcellsportal.com/
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Reese, D. M.
Right arrow Articles by Slamon, D. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Reese, D. M.
Right arrow Articles by Slamon, D. J.
Stem Cells, Vol. 15, No. 1, 1-8, January 1997
© 1997 AlphaMed Press

Concise Reviews

HER-2/neu Signal Transduction in Human Breast and Ovarian Cancer

David M. Reese, Dennis J. Slamon

Division of Hematology/Oncology and Jonsson Comprehensive Cancer Center, UCLA School of Medicine, Los Angeles, California, USA

Key Words. HER-2/neu • erbB receptors • Signal transduction • Breast cancer • Ovarian cancer • Heregulin • Epidermal growth factor

Dr. Dennis J. Slamon, University of California at Los Angeles, Department of Medicine, Division of Hematology/Oncology, 11-934 Factor Building, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.


   Abstract
Top
 Abstract
Introduction
 Receptor Structure
 Receptor Dimerization and...
 Anti-Her-2 Receptor Antibodies
 Conclusions
 References
 
The HER-2/neu proto-oncogene encodes a 185 kDa transmembrane receptor tyrosine kinase with significant sequence homology to other members of the class I receptor tyrosine kinase family. The HER-2/neu gene is amplified and/or overexpressed in 25%-30% of human breast and ovarian cancers, and overexpression of the receptor is associated with poor prognosis. Tyrosine phosphorylation and activation of the HER-2 receptor lead to activation of specific signal transduction pathways in breast and ovarian cancer cells, including the ras/MAP kinase cascade, phosphatidylinositol 3-kinase, and phospholipase C-{gamma}. HER-2/neu signal transduction pathways ultimately converge on the cell nucleus, where the expression of diverse genes is induced after activation of the receptor. A more complete understanding of HER-2/neu signal transduction pathways may allow the development of specific therapeutics for the treatment of those human breast and ovarian cancers containing this alteration.


   Introduction
Top
 Abstract
 Introduction
Receptor Structure
 Receptor Dimerization and...
 Anti-Her-2 Receptor Antibodies
 Conclusions
 References
 
The HER-2/neu proto-oncogene encodes a 185 kDa transmembrane receptor protein with intrinsic tyrosine kinase activity. HER-2/neu was originally identified as a transforming oncogene in chemically induced rat neuroglioblastomas, where a single point mutation in the transmembrane domain of the molecule is sufficient to confer oncogenic activation [1, 2]. In contrast, the receptor is activated in human breast and ovarian cancers through amplification and overexpression of the wild-type gene. This alteration occurs in 25%-30% of cases and is associated with a poor prognosis [3-6]. HER-2/neu may also play a role in the genesis of human gastric, endometrial and salivary gland cancers [7, 8]. Consistent with these clinical observations, overexpression of HER-2/neu in human breast and ovarian cancer cell lines has been shown to increase DNA synthesis and promote cell growth, improve soft agar cloning efficiency and increase tumorigenicity in nude mouse xenograft models [9-11].

The precise mechanism by which HER-2 overexpression transforms cells remains unknown, but presumably involves activation of the signal transduction pathways through which the receptor operates. We review here some of the current concepts regarding HER-2/neu signal transduction as they relate to its role in the pathogenesis of human breast and ovarian malignancies.


   Receptor Structure
Top
 Abstract
 Introduction
 Receptor Structure
Receptor Dimerization and...
 Anti-Her-2 Receptor Antibodies
 Conclusions
 References
 
HER-2/neu is a member of the erbB/epidermal growth factor receptor (EGFR)/class I family of receptor tyrosine kinases (RTKs). All members of this family, which include EGFR, HER-2/neu, HER-3 and HER-4, are single-chain membrane-spanning proteins which have significant sequence homology to one another [12]. The class I RTKs can be distinguished from at least eight other groups of RTKs on the basis of sequence and structural characteristics [13]. The characteristic structural features of class I RTKs include an extracellular ligand-binding domain containing cysteine-rich regions and possible glycosylation sites, an amphipathic transmembrane region, a short intracellular juxtamembrane region, a tyrosine kinase domain and a carboxyl tail which contains critical tyrosine phosphorylation sites [14]. The highest degree of sequence homology (approximately 80% amino acid identity) between HER-2, EGFR and HER-4 lies in the tyrosine kinase domain, suggesting that this region is essential for the signaling function of these molecules [15]. HER-3, by contrast, has substitutions in four important amino acid residues in its tyrosine kinase domain, leading to the suggestion that this receptor may have reduced or absent enzymatic activity [16]. In experimental systems, HER-3 lacks tyrosine kinase activity when expressed alone in insect cells [17] or a pro-B-lymphocyte line [18], although enzymatic activity has been reported when it is overexpressed in mouse fibroblasts or as a chimera with the EGFR extracellular domain [19].

Structural domains other than the tyrosine kinase region may also play an important role in HER-2/neu signal transduction. The cysteine-rich regions of the extracellular portion of the receptor likely undergo significant disulfide bonding, resulting in specific secondary and tertiary structure, which may influence the molecule's interactions with ligand and other receptors [15]. The juxtamembrane region just inside the plasma membrane contains a conserved site (shared with EGFR) for protein kinase C (PKC) phosphorylation, and phosphorylation of PKC results in downregulation of receptor-binding sites and tyrosine kinase activity [20]. The carboxyl tail regions of class I RTKs display the least degree of sequence homology, perhaps allowing for some degree of signaling specificity. Further insights into the relationships between HER-2/neu receptor structure and function will depend on detailed three-dimensional structural data which are not yet available.


   Receptor Dimerization and Tyrosine Phosphorylation
Top
 Abstract
 Introduction
 Receptor Structure
 Receptor Dimerization and...
Anti-Her-2 Receptor Antibodies
 Conclusions
 References
 
The hallmark of class I RTK activation is phosphorylation on specific tyrosine residues lying primarily in the carboxyl terminal portion of the molecule. Traditionally, activation of this class of receptors was thought to require the formation of receptor homodimers, which transphosphorylate one another and subsequently engage proteins involved in the downstream signal transduction process. This model was developed based on studies of the EGFR. In the case of HER-2/neu, however, it has recently become clear that interactions with other members of the class I RTK family are important for receptor activation, and the nature of these heterodimerization events may determine the cellular response to ligand.

Receptor Dimerization
As stated above, the model for class I RTK homodimerization and activation was originally proposed for interactions between the EGFR molecule and its ligands [21]. For EGFR, activation of single receptor molecules is structurally unfavorable, and ligand binding is thought to induce allosteric changes which favor the formation of homodimers [14]. The extracellular domain is sufficient to promote EGFR homodimer formation [22].

Insights into the role of receptor dimerization in HER-2/neu signal transduction first came from studies of the mutated rat neu protein. A single amino acid substitution within the transmembrane region of the molecule leads to constitutive receptor dimerization and increases in basal tyrosine phosphorylation [23, 24]. This correlates with increased kinase enzymatic activity and phosphorylation of several intracellular targets [25]. Consistent with these data, expression of abbreviated transmembrane fragments of p185, along with the oncogenic form of the neu protein, reduced cell proliferation and inhibited transformation, presumably through inhibition of effective receptor dimerization [26].

Based on these observations, it has been suggested that in human cancer cells overexpressing wild-type HER-2/neu, the receptor dimerizes spontaneously due to the large number of molecules present [27]. In support of this hypothesis, human breast and ovarian cancer cells overexpressing HER-2/neu have high levels of basal tyrosine phosphorylation [28]. Direct study of HER-2 receptor dimerization has been hampered until recently, however, by the lack of a specific ligand known to activate the receptor.

In 1992, heregulin (HRG)/neu differentiation factor (NDF) was identified as a candidate ligand for HER-2/neu on the basis of its ability to induce tyrosine phosphorylation of the molecule in human breast cancer cells [29, 30]. HRG, a 45 kDa secreted protein which is similar to but distinct from other members of the EGF ligand family, exists in multiple isoforms and is known variously as NDF, acetylcholine receptor-inducing activity and glial growth factor, depending on its cell type of origin and reported effects on target cells [29-32]. Despite the fact that it was discovered due to its ability to induce HER-2/neu tyrosine phosphorylation, HRG does not bind directly to HER-2/neu alone. Rather, HRG binds specifically to either the HER-3 or HER-4 molecules alone with relatively low affinity [33, 34]. HER-2, however, is capable of dimerizing with HER-3 and these two molecules together reconstitute a high affinity receptor for ligand [35]. Thus it has been suggested that activation of HER-2/neu may occur only via heterodimerization with other members of the class I RTK family [16], and there is accumulating experimental evidence that this is indeed the case.

It has been known for some time that EGF is also capable of inducing the tyrosine phosphorylation of HER-2/neu in cells which express both receptors, presumably through transphosphorylation of HER-2 by an activated EGFR [36, 37]. The EGFR interaction with HER-2/neu may, in fact, be crucial. The expression of a kinase-negative HER-2 mutant is capable of suppressing normal EGFR signaling after EGF stimulation in a dominant negative fashion [38], and single-chain intracellular retention of HER-2/neu in T47D human breast cancer cells (which express all four class I RTKs at moderate levels) markedly impairs signaling induced by EGF and NDF [39].

HER-2/neu can and does interact with the HER-3 and HER-4 molecules. Evidence for this is found in COS-7 cells expressing HER-2 and HER-3, which form a high affinity receptor for HRG, and in which both receptors can be crosslinked to ligand [35]. In NIH 3T3 cells, neither HER-2 nor HER-3 when expressed alone undergo tyrosine phosphorylation in response to HRG, but when expressed together both are phosphorylated and are associated with enhanced transformation [40]. Likewise, HRG induces the tyrosine phosphorylation of HER-4 but not HER-2 when these receptors are expressed singly in T lymphoblasts, whereas HER-2 is phosphorylated when they are coexpressed [41].

On the basis of these observations, a new model describing HER-2 interactions with the other class I RTKs has been proposed (Fig. 1Go) [16]. According to this scheme, HER-2/neu forms functional receptor heterodimers with each of the other class I RTKs in response to the EGF and HRG families of ligands. HER-2 heterodimerization with other class I RTKs may be an obligate event because as yet there is no known specific ligand for the HER-2/neu receptor. In addition, coexpression of different combinations of class I RTKs with HER-2 may enhance the specificity and expand the repertoire of downstream signaling events available in epithelial cells containing these receptors.



View larger version (7K):
[in this window]
[in a new window]
  		Figure 1. Model for HER-2 interactions with other erbB receptors in human breast cancer. Members of the EGF and HRG family of ligands bind to erbB receptors other than HER-2, which interacts with them in receptor heterodimer pairs to initiate downstream signaling events.

 
Tyrosine Phosphorylation
The sine qua non of class I RTK activation is the phosphorylation of discrete tyrosine sites in the carboxyl terminus of the receptor. In fact, signal transduction by class I growth factor receptors absolutely requires tyrosine kinase activity and tyrosine autophosphorylation [14]. In human breast and ovarian cancer cells, overexpression of HER-2/neu increases basal receptor tyrosine phosphorylation to levels greater than any other cellular substrate, and the degree of HER-2 tyrosine phosphorylation generally correlates with effects on cellular transformation in a dose-dependent fashion [42].

Specific tyrosine sites in the carboxyl tail of HER-2/neu have been identified which may be important for HER-2 signal transduction. Experiments with NIH 3T3 cells expressing human HER-2/neu molecules containing single or multiple mutations in selected carboxyl tyrosine residues show that individual amino acid substitutions generally have no effect on the ability of HER-2 to transform these cells, while the presence of multiple mutations inhibited focal growth in monolayers and was associated with a decrease in HER-2 tyrosine phosphorylation [43]. In addition, studies of a human HER-2 protein containing a transmembrane amino acid mutation similar to the lesion found in oncogenic rat neu protein demonstrated that the additional mutation of tyrosine residue Y1248 reduced the transforming ability of this molecule [27]. The homologous tyrosine residue in the rat neu protein is also essential for the transforming capability of this receptor [44].

While there is substantial evidence implicating specific tyrosine sites in the transforming ability of HER-2/neu, some studies have suggested that deletion of these amino acids does not wholly compromise the ability of HER-2 to transform cells or activate downstream signaling molecules. Indeed, HER-2 mutants with substitutions in single intracellular tyrosine sites retain the ability to transform NIH 3T3 cells and tyrosine phosphorylate Shc, an adaptor molecule which links activated RTKs with the ras/MAP kinase intracellular signal transduction pathway (see below) [45, 46]. In addition, it has been observed that the ability of anti-HER-2 monoclonal antibodies to induce receptor tyrosine phosphorylation may not correlate with their effects on cell proliferation [47], implying that events in addition to simple tyrosine phosphorylation, such as specific conformational changes, may be necessary to effectively activate the receptor. Understanding the specific importance of tyrosine phosphorylation will ultimately require the elucidation of the downstream signaling pathways through which HER-2/neu operates, as well as analysis of their activation in cells bearing HER-2 molecules with alterations in specific tyrosine residues.

Intracellular Signaling Mechanisms
The activation of growth factor receptors leads to the phosphorylation and activation of multiple second messengers within normal cells. Subversion of these intracellular signaling pathways is a common occurence in many human malignancies. Many downstream signaling molecules complex with activated RTKs via src homology 2 (SH2) domains, short modules of approximately 100 amino acids which bind with high affinity to phosphotyrosine residues present in specific amino acid sequences [48]. SH2 domains are present in a number of cellular proteins involved in signal transduction, including enzymes, direct regulators of gene transcription, and molecules which function as adaptors for important protein-protein interactions [48]. Many SH2 domain-containing proteins also have src homology 3 (SH3) domains, which contain a binding site for proline-rich sequences believed to be involved in specific protein-protein interactions [49]. A number of substrates for the HER-2/neu tyrosine kinase containing SH2 and SH3 domains have been identified in human breast and ovarian cancer cells. In addition, other diverse intracellular signaling molecules may play a role in HER-2 signal transduction. An overview of putative HER-2/neu signaling pathways is presented in Figure 2Go.



View larger version (17K):
[in this window]
[in a new window]
  		Figure 2. Postulated HER-2 signal transduction pathways. Activation of the HER-2 receptor induces tyrosine phosphorylation on specific tyrosine residues (YP) in the carboxyl tail of the molecule. Downstream signaling proteins with SH2 domains bind to YP residues in the context of specific flanking amino acid sequences and are phosphorylated. Activation of intracellular signaling pathways occurs and culminates in transcription of nuclear genes. For explanation of individual pathways, see text.

 
The ras/MAP Kinase Cascade
Elucidation of the ras-activated intracellular signaling cascade represents a milestone in modern cell biology. This is a critical pathway for a number of signals transduced inside the cell, many of which are growth-regulating signals. Moreover, ras genes, which encode small proteins with intrinsic GTPase activity, are the most frequently mutated oncogenes in human cancers [50], leading to the concept that this pathway is a common target for many transforming and/or carcinogenic agents. Stimulation of the ras pathway ultimately leads to the activation of mitogen-activated protein (MAP) kinase, an enzyme with a number of intracellular targets including nuclear transcription factors [51]. After tyrosine receptors are phosphorylated, the adaptor molecules grb2 and/or Shc bind to the carboxyl tail of the receptor through SH2 domains [52, 53]. The guanine-nucleotide exchange factor, Sos, next interacts with Shc/grb2 via the grb2 SH3 domain, and this complex is brought to the receptor at the cytoplasmic surface of the plasma membrane. Sos subsequently catalyzes the dissociation of GDP from ras, permitting the formation of an activated ras-GTP complex [54]. Ras-GTP then (through an unknown mechanism which may involve other proteins) activates raf-1, a serine-threonine kinase. raf-1 in turn phosphorylates and activates MEK, a specific threonine-tyrosine kinase which activates MAP kinase [55].

There is evidence that activation of the ras/MAP kinase pathway is important in HER-2/neu signal transduction. In T47D human breast cancer cells, which express all four members of the class I RTK family, Shc phosphorylation and MAP kinase activation occur after treatment with NDF. The degree of MAP kinase activation is markedly reduced, however, when HER-2 expression is decreased by single-chain antibody-mediated intracellular retention of the molecule in the endoplasmic reticulum [39]. Shc and grb2 also bind to HER-2 in both NIH 3T3 cells and human breast cancer cells engineered to overexpress the human HER-2/neu receptor, and Sos can be detected in HER-2 immunoprecipitates [45, 56], presumably indicating activation and complexing of the molecules involved in the ras cascade. We have also observed increases in MAP kinase activity after stimulation of HER-2-overexpressing human breast and ovarian cancer cells with HRG [Arboleda, Reese, Slamon, unpublished observations], and this increase is associated with enhanced transcription of the immediate-early response genes c-fos and EGR1 [57].

Activation of the ras pathway may occur in HER-2-expressing cells through protein interactions which do not involve SH2 domains. Recently, a non-SH2 phosphotyrosine-binding (PTB) domain has been described in the Shc molecule [58], and it appears that HER-2 can interact with this domain [59]. Further studies on the binding of HER-2 to Shc and the activation of the ras cascade are required to determine the relative importance of SH2 and PTB domains to Shc-HER-2/neu interactions.

Phospholipase C-{gamma}
The phosphodiesterase phospholipase C-{gamma} (PLC{gamma}) also binds to activated RTKs via SH2 domains [60]. Phosphorylation of PLC{gamma} activates its enzymatic activity, generating the second messengers inositol 1,4,5-triphosphate and diacylglycerol, which are involved in mobilization of intracellular calcium and possibly activation of raf-1 via protein kinase C [60]. In cells overexpressing human HER-2/neu, PLC{gamma} physically interacts with and is phosphorylated by HER-2 [61]. In addition, PLC{gamma} coimmunoprecipitates with the oncogenic rat neu protein in cells expressing this receptor, and activation of the PLC{gamma} enzyme depends on its phosphorylation by an activated neu receptor [62]. These results indicate that HER-2/neu can physically associate with and tyrosine phosphorylate PLC{gamma}. The functional relevance of this interaction, however, remains to be determined.

Phosphatidylinositol 3-Kinase
Phosphatidylinositol 3-kinase (PI3K) is an enzyme which phosphorylates phosphatidylinositol (PI) and related substrates, generating intracellular second messengers which may have diverse effects on target cells [63]. PI3K is composed of two subunits, a 110 kDa catalytic protein and an 85 kDa regulatory subunit which contains SH2 and SH3 domains [64]. This 85 kDa regulatory subunit interacts with and is phosphorylated by activated growth factor receptors, enhancing the enzymatic activity of the 110 kDa catalytic subunit [63, 64].

PI3K is a substrate for the oncogenic rat neu protein, and neu activation increases PI3K lipid kinase activity [65]. In human breast cancer cells, the p85 subunit of PI3K is phosphorylated by HER-2/neu after ligand-stimulated activation of the receptor, and p85 can be coimmunoprecipitated with activated HER-2/neu [66]. It is possible that activation of PI3K by HER-2/neu is actually mediated by HER-3 in a receptor heterodimer complex, since the HER-3 molecule has a large number of binding domains predicted to interact with p85 and may be unique among human class I RTKs in its ability to couple to PI3K [16, 67, 68]. It has been shown that induction of PI3K lipid kinase activity after stimulation of EGFR with EGF requires interaction between EGFR and HER-3 [69], and it is likely that the same is true in the case of HER-2/neu, although there is no current experimental evidence for this.

Nuclear Transcription Factors
Diverse intracellular signaling pathways ultimately converge on the cell nucleus, where the expression of genes which regulate cellular proliferation and differentiation is tightly coordinated. A number of nuclear transcription factors have been identified as targets of HER-2/neu signal transduction pathways, and induction of their expression may represent the most important result of activation of the HER-2 receptor.

The immediate early nuclear transcription genes, including c-fos, c-jun and EGR1, are rapidly upregulated in response to a variety of stimuli during the G0/G1 stage of the cell cycle, implicating them as fundamental components of the mitogenic response [70]. Treatment of HER-2/neu-expressing T47D human breast cancer cells with NDF results in the transient induction of c-fos and c-jun expression, and downregulation of HER-2 expression blocks this response [39]. In MCF-7 breast cancer cells engineered to overexpress human HER-2/neu, expression of c-fos, EGR1 and the early response gene c-myc can also be induced by HRG, as well as some anti-HER-2 monoclonal antibodies [57]. It is likely that induction of c-fos expression occurs through a ras-dependent pathway because in related RTK systems, mutations of various components of the ras/MAP kinase cascade markedly reduce or eliminate c-fos expression in response to serum growth factors [70-72]. Conversely, the induction of c-jun and c-myc expression may occur through ras-independent signaling mechanisms. A specific pathway leading to the activation of Jun kinase, a member of the MAP kinase family, has recently been identified and is activated in response to some serum growth factors [73, 74]. In addition, there is evidence that induction of c-myc expression after treatment of NIH 3T3 cells with EGF requires functional src, a nonreceptor tyrosine kinase which may couple activated RTKs with induction of c-myc expression [75]. The relevance of these pathways to HER-2/neu signal transduction is currently under investigation.


   Anti-Her-2 Receptor Antibodies
Top
 Abstract
 Introduction
 Receptor Structure
 Receptor Dimerization and...
 Anti-Her-2 Receptor Antibodies
Conclusions
 References
 
HER-2/neu signal transduction has also been studied using antibodies directed against the extracellular domain of the receptor. A variety of antibodies have been generated which have antiproliferative effects on cells overexpressing the HER-2/neu receptor. Some of these antibodies may activate HER-2 signal transduction pathways.

The murine monoclonal antibody 4D5 is directed at the extracellular juxtamembrane region of HER-2/neu and has significant antiproliferative effects on breast and ovarian cancer cells which overexpress this receptor [76-79]. Understanding the effects of the 4D5 antibody on HER-2/neu signal transduction is of particular interest because a humanized version of the molecule [80] has shown promise in the treatment of patients with metastatic breast cancer [81, 82]. In vitro, 4D5 induces the tyrosine phosphorylation of HER-2/neu and leads to partial downregulation of HER-2 receptor levels in target cells [76]. In addition, 4D5 induces PI3K and PI4K lipid kinase activity in breast cancer cells stimulated with the antibody [83]. We have observed that both HRG and 4D5 induce the tyrosine phosphorylation of a comparable suite of downstream signaling molecules including Shc, the p85 subunit of PI3K and PLC{gamma} [Arboleda, Reese, Slamon, unpublished observations], raising the question as to how molecules with opposite biologic effects (cell proliferation versus growth inhibition) differ in their activation of signal transduction pathways.

Other antibodies have been produced which interact with the extracellular domain of HER-2/neu [47, 84, 85]. Shawver et al. studied the effects of a panel of monoclonal anti-HER-2 antibodies on cell proliferation and HER-2/neu signal transduction and found that, while the antibodies varied in their ability to inhibit the growth of HER-2/neu-overexpressing cells and to induce tyrosine phosphorylation of the receptor, there was not a universal correlation between ligand-like effects of the antibodies and their effects on cell proliferation [47]. Other antireceptor antibodies may induce differentiation of HER-2-expressing breast epithelial cells [84], although the mechanisms by which these effects are mediated remain unknown. One potential explanation for the diverse effects of ligand and antireceptor antibodies is that bivalent antibody may cause the formation of obligate HER-2/neu homodimers, which may be capable of tyrosine phosphorylating some intracellular targets but may not generate effective downstream signaling comparable to HER-2 heterodimerization with other members of the class I RTK family (see above). Another possibility is that antibodies and ligand effectively activate different sets of intracellular signaling molecules. Elucidating these differences should prove useful in determining which intracellular signaling pathways are crucial for effective signal transduction through the HER-2 receptor, and may aid in the design of new therapeutic agents directed at HER-2/neu or its signaling pathway.


   Conclusions
Top
 Abstract
 Introduction
 Receptor Structure
 Receptor Dimerization and...
 Anti-Her-2 Receptor Antibodies
 Conclusions
References
 
The HER-2/neu oncogene is amplified and/or overexpressed in 25%-30% of human breast and ovarian cancers, and its overexpression portends a poor prognosis for those patients whose tumors contain this alteration. Activation of specific HER-2/neu signal transduction pathways correlates with the ability of HER-2 to transform breast and ovarian epithelial cells, although characterization of the precise routes through which HER-2 signal transduction is mediated remains incomplete. Improved understanding of HER-2/neu signal transduction pathways may lead to the identification of novel therapeutic targets in the treatment of human breast and ovarian cancer.


   Acknowledgments
 
This work was supported in part by grants 1K12 CA01714 (D.M.R.), R01 CA36827 (D.J.S.), the U.S. Army Breast Cancer Research Program DAMD 17-94-J-4118 (D.J.S.), and the Revlon/UCLA Women's Cancer Research Fund.


   References
Top
 Abstract
 Introduction
 Receptor Structure
 Receptor Dimerization and...
 Anti-Her-2 Receptor Antibodies
 Conclusions
 References
 

  1. Shih C, Padhy L, Murray M et al. Transforming genes of carcinomas and neuroblastomas introduced into mouse fibroblasts. Nature 1981;260:261-264.

  2. Bargmann C, Hung M-C, Weinberg R. Multiple independent activations of the neu oncogene by a point mutation altering the transmembrane domain of p185. Cell 1986;45:649-657.[Medline]

  3. Slamon DJ, Clark G, Wong S et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987;235:177-181.[Abstract/Free Full Text]

  4. Slamon DJ, Godolphin W, Jones L et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 1989;244:707-711.[Abstract/Free Full Text]

  5. Venter D, Kumar S, Tuzi N et al. Overexpression of the c-erbB-2 oncoprotein in human breast carcinomas: immunohistochemical assessment correlates with gene amplification. Lancet 1987;2:69-72.[Medline]

  6. Natali P, Nicotra M, Brigotti A et al. Expression of the p185 encoded by HER2 oncogene in normal and transformed human tissues. Int J Cancer 1990;45:457-461.[Medline]

  7. Yonemura Y, Ninomiya I, Yamaguchi A et al. Evaluation of immunoreactivity for erbB-2 protein as a marker of poor short-term prognosis in gastric cancer. Cancer Res 1991;51:1034-1038.[Abstract/Free Full Text]

  8. Press MF, Pike MC, Hung G et al. Amplification and overexpression of HER-2/neu in carcinomas of the salivary gland: correlation with poor prognosis. Cancer Res 1994;54:5675-5682.[Abstract/Free Full Text]

  9. Hudziak RM, Schlessinger J, Ullrich A. Increased expression of the putative growth factor receptor p185 HER2 causes transformation and tumor genesis of NIH 3T3 cells. Proc Natl Acad Sci USA 1987;84:7159-7163.[Abstract/Free Full Text]

  10. Di Fiore P, Pierce J, Kraus M et al. ErbB-2 is a potent oncogene when overexpressed in NIH/3T3 cells. Science 1987;237:178-182.[Abstract/Free Full Text]

  11. Pietras R, Arboleda J, Reese D et al. HER-2 tyrosine kinase pathway targets estrogen receptor and promotes hormone-independent growth in human breast cancer cells. Oncogene 1995;10:2345-2446.

  12. Schlessinger J, Ullrich A. Growth factor signalling by receptor tyrosine kinases. Neuron 1992;9:383-391.[Medline]

  13. Fantl W, Johnson D, Williams LT. Signalling by receptor tyrosine kinases. Annu Rev Biochem 1993;62:453-481.[Medline]

  14. Ullrich A, Schlessinger J. Signal transduction by receptors with tyrosine kinase activity. Cell 1990;61:203-212.[Medline]

  15. Earp HS, Dawson TL, Li X et al. Heterodimerization and functional interaction between EGF receptor family members: a new signaling paradigm with implications for breast cancer research. Breast Cancer Res Treat 1995;35:115-132.[Medline]

  16. Carraway K, Cantley L. A neu acquaintance for erbB3 and erbB4: a role for receptor heterodimerization in growth signaling. Cell 1994;78:5-8.[Medline]

  17. Guy PM, Platko JV, Cantley LC et al. Insect cell-expressed p180erbB3 possesses an impaired tyrosine kinase activity. Proc Natl Acad Sci USA 1994;91:8132-8136.[Abstract/Free Full Text]

  18. Riese D, van Raaij T, Plowman G et al. The cellular response to neuregulins is governed by complex interactions of the erbB receptor family. Mol Cell Biol 1995;15:5770-5776.[Abstract]

  19. Kraus MH, Fedi P, Starks V et al. Demonstration of ligand-dependent signaling by the erbB3 tyrosine kinase and its constitutive activation in human breast tumor cells. Proc Natl Acad Sci USA 1993;90:2900-2904.[Abstract/Free Full Text]

  20. Lin C, Chen W, Lazar C et al. Protein Kinase C phosphorylation at Thr 654 of the unoccupied EGF receptor and EGF binding regulate functional receptor loss by independent mechanisms. Cell 1986;44:839-848.[Medline]

  21. Yarden Y, Schlessinger J. Self-phosphorylation of epidermal growth factor receptor: evidence for a model of intermolecular allosteric activation. Biochemistry 1987;26:1434-1442.[Medline]

  22. Spivak-Kroizman T, Rotin D, Pinchasi D et al. Heterodimerization of c-erbB2 with different epidermal growth factor receptor mutants elicits stimulatory or inhibitory responses. J Biol Chem 1992;267:8056-8063.[Abstract/Free Full Text]

  23. Weiner DB, Liu J, Cohen JA et al. A point mutation in the neu oncogene mimics ligand induction of receptor aggregation. Nature 1989;339:230-231.[Medline]

  24. Stern DF, Kamps MP, Lao H. Oncogenic activation of p185neu stimulates tyrosine phosphorylation in vivo. Mol Cell Biol 1988;8:3969-3973.[Abstract/Free Full Text]

  25. Bargmann C, Weinberg R. Increased tyrosine kinase activity associated with the protein encoded by the activated neu oncogene. Proc Natl Acad Sci USA 1988;85:5394-5398.[Abstract/Free Full Text]

  26. Lofts F, Hurst HC, Sternberg MJ et al. Specific short transmembrane sequences can inhibit transformation by the mutant neu growth factor receptor in vitro and in vivo. Oncogene 1993;8:2813-2820.[Medline]

  27. Akiyama T, Matsuda S, Namba Y et al. The transforming potential of the c-erbB-2 protein is regulated by its autophosphorylation at the carboxyl-terminal domain. Mol Cell Biol 1991;11:833-842.[Abstract/Free Full Text]

  28. DiGiovanna MP, Stern DF. Activation state-specific monoclonal antibody detects tyrosine phosphorylated p185neu/erbB-2 in a subset of human breast tumors overexpressing this receptor. Cancer Res 1995;55:1946-1955.[Abstract/Free Full Text]

  29. Holmes W, Sliwkowski M, Akita R et al. Identification of heregulin, a specific activator of p185erbB2. Science 1992;256:1205-1210.[Abstract/Free Full Text]

  30. Peles E, Bacus S, Koski R et al. Isolation of the Neu/HER2 stimulatory ligand: a 44kd glycoprotein that induces differentiation of mammary tumor cells. Cell 1992;69:205-216.[Medline]

  31. Falls DG, Rosen KM, Cortas G et al. ARIA, a protein that stimulates acetylcholine receptor synthesis, is a member of the neu ligand family. Cell 1993;72:801-815.[Medline]

  32. Marchionni MA, Goodearl ADJ, Chen MS et al. Glial growth factors are alternatively spliced erbB2 ligands expressed in the nervous system. Nature 1993;362:312-318.[Medline]

  33. Carraway K, Sliwkowski M, Akita R et al. The erbB3 gene product is a receptor for heregulin. J Biol Chem 1994;269:14303-14306.[Abstract/Free Full Text]

  34. Plowman G, Green J, Culouscou J-M et al. Heregulin induces tyrosine phosphorylation of HER4/p180erbB4. Nature 1993;366:473-475.[Medline]

  35. Sliwkowski M, Schaefer G, Akita R et al. Coexpression of erbB2 and erbB3 proteins reconstitutes a high affinity receptor for heregulin. J Biol Chem 1994;269:14661-14665.[Abstract/Free Full Text]

  36. King C, Borrello I, Bellot F et al. EGF binding to its receptor triggers a rapid tyrosine phosphorylation of the erbB-2 protein in the mammary tumor cell line SKBR3. EMBO J 1988;7:1647-1651.[Medline]

  37. Wada T, Qian X, Greene M. Intermolecular association of the p185neu protein and EGF receptor modulates EGF receptor function. Cell 1990;61:1339-1347.[Medline]

  38. Qian X, Dougall WC, Hellmann ME et al. Kinase-deficient neu protein suppresses epidermal growth factor receptor function and abolishes cell transformation. Oncogene 1994;9:1507-1514.[Medline]

  39. Graus-Porta D, Beerli R, Hynes N. Single-chain antibody-mediated intracellular retention of erbB-2 impairs neu differentiation factor and epidermal growth factor signaling. Mol Cell Biol 1995;15:1182-1191.[Abstract]

  40. Wallasch C, Weiss FU, Niederfellner G et al. Heregulin-dependent regulation of HER2/neu oncogenic signaling by heterodimerization with HER3. EMBO J 1995;14:4267-4275.[Medline]

  41. Plowman G, Culouscou J-M, Whitney G et al. Ligand-specific activation of HER4/p180erbB4, a fourth member of the epidermal growth factor receptor family. Proc Natl Acad Sci USA 1993;90:1746-1750.[Abstract/Free Full Text]

  42. Chazin V, Kaleko M, Miller A et al. Transformation mediated by the human HER-2 gene independent of the epidermal growth factor receptor. Oncogene 1992;7:1859-1866.[Medline]

  43. Segatto O, Lonardo F, Pierce JH et al. The role of autophosphorylation in modulation of erbB-2 transforming function. New Biol 1990;2:187-195.[Medline]

  44. Mikami Y, Davis J, Dobashi K et al. Carboxyl-terminal deletion and point mutations decrease the transforming potential of the activated rat neu oncogene product. Proc Natl Acad Sci USA 1992;89:7335-7339.[Abstract/Free Full Text]

  45. Segatto O, Pelicci G, Giuli S et al. Shc products are substrates for erbB-2 kinase. Oncogene 1993;8:2105-2112.[Medline]

  46. Xie Y, Li K, Hung MC. Tyrosine phosphorylation of shc protein and formation of shc/grb2 complex correlate to the transformation of NIH 3T3 cells mediated by the point-mutation activated neu. Oncogene 1995;10:2409-2413.[Medline]

  47. Shawver L, Mann E, Elliger S et al. Ligand-like effects induced by anti-c-erbB-2 antibodies do not correlate with and are not required for growth inhibition of human carcinoma cells. Cancer Res 1994;54:1367-1373.[Abstract/Free Full Text]

  48. Koch C, Anderson D, Moran M et al. SH2 and SH3 domains: elements that control interactions of cytoplasmic signaling proteins. Science 1991;252:668-674.[Abstract/Free Full Text]

  49. Pawson T, Gish D. SH2 and SH3 domains: from structure to function. Cell 1992;71:359-362.[Medline]

  50. Bos JL. Ras oncogenes in human cancer: a review. Cancer Res 1989;49:4682-4689.[Abstract/Free Full Text]

  51. Johnson G, Vaillancourt R. Sequential protein kinase reactions controlling cell growth and differentiation. Curr Opin Cell Biol 1994;6:230-238.[Medline]

  52. Pelicci G, Lanfrancone L, Grignani J et al. A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction. Cell 1992;70:93-104.[Medline]

  53. Egan SE, Giddings BW, Brooks MW et al. Association of Sos Ras exchange protein with grb2 is implicated in tyrosine kinase signal transduction and transformation. Nature 1993;363:45-51.[Medline]

  54. Li N, Batzer A, Daly R et al. Guanine-nucleotide releasing factor hSos1 binds to grb2 and links receptor tyrosine kinases to ras signalling. Nature 1993;368:85-88.

  55. Lange-Carter C, Pleiman C, Gardner A et al. A divergence in the MAP kinase regulatory network defined by MEK kinase and raf. Science 1993;260:315-319.[Abstract/Free Full Text]

  56. Janes PW, Daly RJ, deFazio A et al. Activation of the ras signalling pathway in human breast cancer cells overexpressing erbB-2. Oncogene 1994;9:3601-3608.[Medline]

  57. Levin W. Transcriptional activation in response to the HER-2/neu stimulatory ligand heregulin and inhibitory antibody 4D5 in human breast cancer cells. Master's thesis 1995. University of California, Los Angeles.

  58. Kavanaugh WM, Williams LT. An alternative to SH2 domains for binding tyrosine-phosphorylated proteins. Science 1994;266:1862-1865.[Abstract/Free Full Text]

  59. Kavanaugh WM, Turck CW, Williams LT. PTB domain binding to signaling proteins through a sequence motif containing phosphotyrosine. Science 1995;268:1177-1179.[Abstract/Free Full Text]

  60. Noh DY, Shin SH, Rhee SG. Phosphoinositide-specific phospholipase C and mitogenic signaling. Biochim Biophys Acta 1995;1242:99-113.[Medline]

  61. Fazioli F, Kim U-H, Rhee S et al. The erbB-2 mitogenic signaling pathway: tyrosine phosphorylation of phospholipase C-g and GTP-ase activating protein does not correlate with erbB-2 mitogenic potency. Mol Cell Biol 1991;11:2040-2048.[Abstract/Free Full Text]

  62. Peles E, Ben-Levy R, Or E et al. Oncogenic forms of the neu/HER2 tyrosine kinase are permanently coupled to phospholipase Cg. EMBO J 1991;10:2077-2086.[Medline]

  63. Fry MJ, Waterfield MD. Structure and function of phosphatidylinositol 3-kinase: a potential second messenger in systems involved in growth control. Philos Trans R Soc Lond B Biol Sci 1993;340:337-344.[Medline]

  64. Kapeller R, Cantley LC. Phosphatidylinositol 3-kinase. Bioessays 1994;16:565-576.[Medline]

  65. Peles E, Lamprecht R, Ben-Levy R et al.Regulated coupling of the neu receptor to phosphatidylinositol 3-kinase and its release by oncogenic activation. J Biol Chem 1992;267:12266-12274.[Abstract/Free Full Text]

  66. Beerli R, Graus-Porta D, Woods-Cook K et al. Neu differentiation factor activation of ErbB-3 and ErbB-4 is cell specific and displays a differential requirement for ErbB-2. Mol Cell Biol 1995;15:6496-6505.[Abstract]

  67. Fedi P, Pierce J, Di Fiore P et al. Efficient coupling with phosphatidylinositol 3-kinase, but not phospholipase Cg or GTP-ase activating protein, distinguishes erbB-3 signaling from that of other erbB/EGFR family members. Mol Cell Biol 1994;14:3550-3558.[Abstract/Free Full Text]

  68. Prigent S, Gullick W. Identification of c-erbB-3 binding sites for phosphatidylinositol 3-kinase and SHC using an EGF receptor/c-erbB-3 chimera. EMBO J 1994;13:2831-2841.[Medline]

  69. Soltoff S, Carraway K, Prigent S et al. ErbB-3 is involved in activation of phosphatidylinositol 3-kinase by epidermal growth factor. Mol Cell Biol 1994;14:3550-3558.

  70. Lewin B. Oncogenic conversion by regulatory changes in transcription factors. Cell 1991;64:303-312.[Medline]

  71. Mansour S, Matten W, Hermann A et al. Transformation of mammalian cells by constitutively active MAP kinase kinase. Science 1994;265:966-970.[Abstract/Free Full Text]

  72. Minden A, Lin A, McMahon M et al. Differential activation of ERK and JNK mitogen-activated protein kinases by raf-1 and MEKK. Science 1994;266:1719-1723.[Abstract/Free Full Text]

  73. Xia Z, Dickens M, Raingeaud J et al. Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 1995;270:1326-1331.[Abstract/Free Full Text]

  74. Raitano A, Halpern J, Hanbuch T et al. The Bcr-abl leukemia oncogene activates Jun kinase and requires Jun for transformation. Proc Natl Acad Sci USA 1995;92:11746-11750.[Abstract/Free Full Text]

  75. Barone V, Courtneidge S. Myc but not fos rescue of PDGF signalling block caused by kinase inactive src. Nature 1995;378:509-511.[Medline]

  76. Kumar R, Shepard HM, Mendelsohn J. Regulation of phosphorylation of the c-erbB-2 /HER-2 gene product by a monoclonal antibody and serum growth factors in human mammary carcinoma cells. Mol Cell Biol 1991;11:979-986.[Abstract/Free Full Text]

  77. Lewis G, Figari I, Fendly B et al. Differential responses of human tumor cell lines to anti-p185HER2 monoclonal antibodies. Cancer Immunol Immunother 1993;37:255-263.[Medline]

  78. Pietras R, Fendly B, Chazin V et al. Antibody to HER-2/neu receptor blocks DNA repair after cisplatin in human breast and ovarian cancer cells. Oncogene 1994;9:1829-1838.[Medline]

  79. Hudziak R, Lewis G, Winget M et al. p185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis. Mol Cell Biol 1989;9:1165-1172.[Abstract/Free Full Text]

  80. Carter P, Presta L, Gorman C et al. Humanization of an anti-p185HER2 for human cancer therapy. Proc Natl Acad Sci USA 1992;89:4285-4289.[Abstract/Free Full Text]

  81. Pegram M, Lipton A, Pietras R et al. Phase II study of intravenous recombinant humanized anti-p185HER-2 monoclonal antibody (rhuMAb HER-2) plus cisplatin in patients with HER-2/neu overexpressing metastatic breast cancer. Proc Am Soc Clin Oncol 1995;14:103.

  82. Baselga J, Tripathy D, Mendelsohn J et al. Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol 1996;14;737-744.[Abstract/Free Full Text]

  83. Scott G, Dodson J, Montgomery P et al. p185HER2 signal transduction in breast cancer cells. J Biol Chem 1991;266:14300-14305.[Abstract/Free Full Text]

  84. Hawerth I, Wels W, Marte B et al. Monoclonal antibodies against the extracellular domain of the erbB-2 receptor function as partial ligand agonists. J Biol Chem 1992;267:15160-15167.[Abstract/Free Full Text]

  85. Wada T, Myers J, Kokai Y et al. Anti-receptor antibodies reverse the phenotype of cells transformed by two interacting proto-oncogene encoded receptor proteins. Oncogene 1990;5:489-495.[Medline]

accepted for publication August 9, 1996.



This article has been cited by other articles:


Home page
 Cancer Res.Home page
A. Scardino, M. Alimandi, P. Correale, S. G. Smith, R. Bei, H. Firat, M. G. Cusi, O. Faure, S. Graf-Dubois, G. Cencioni, et al.
A Polyepitope DNA Vaccine Targeted to Her-2/ErbB-2 Elicits a Broad Range of Human and Murine CTL Effectors to Protect against Tumor Challenge
Cancer Res., July 15, 2007; 67(14): 7028 - 7036.
[Abstract] [Full Text] [PDF]

Home page
 Stem CellsHome page
Y.-J. Kang, S.-J. Yang, G. Park, B. Cho, C.-K. Min, T.-Y. Kim, J.-S. Lee, and I.-H. Oh
A Novel Function of Interleukin-10 Promoting Self-Renewal of Hematopoietic Stem Cells
Stem Cells, July 1, 2007; 25(7): 1814 - 1822.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
S. Pervin, R. Singh, E. Hernandez, G. Wu, and G. Chaudhuri
Nitric Oxide in Physiologic Concentrations Targets the Translational Machinery to Increase the Proliferation of Human Breast Cancer Cells: Involvement of Mammalian Target of Rapamycin/eIF4E Pathway
Cancer Res., January 1, 2007; 67(1): 289 - 299.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
Y.-J. Chung, B.-B. Park, Y.-J. Kang, T.-m. Kim, C. J. Eaves, and I.-H. Oh
Unique effects of Stat3 on the early phase of hematopoietic stem cell regeneration
Blood, August 15, 2006; 108(4): 1208 - 1215.
[Abstract] [Full Text] [PDF]

Home page
 J Biomol ScreenHome page
J. Wei, Y. Liu, S. Yang, J. Xu, H. Kong, B. Han, Y. Bao, Y. Wu, W. Yin, W. Li, et al.
Screening of Single-Chain Variable Fragments against TSP50 from a Phage Display Antibody Library and Their Expression as Soluble Proteins
J Biomol Screen, August 1, 2006; 11(5): 546 - 552.
[Abstract] [PDF]

Home page
 Ann. Surg. Oncol.Home page
S. D. Nathanson, R. Slater, D. DeBruyn, A. Kapke, and M. Linden
HER-2/neu Expression in Primary Breast Cancer With Sentinel Lymph Node Metastasis
Ann. Surg. Oncol., February 1, 2006; 13(2): 205 - 213.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
N. Kroger, K. Milde-Langosch, S. Riethdorf, C. Schmoor, M. Schumacher, A. R. Zander, and T. Loning
Prognostic and Predictive Effects of Immunohistochemical Factors in High-Risk Primary Breast Cancer Patients
Clin. Cancer Res., January 1, 2006; 12(1): 159 - 168.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
H. Okano, H. Shinohara, A. Miyamoto, K. Takaori, and N. Tanigawa
Concomitant Overexpression of Cyclooxygenase-2 in HER-2-Positive on Smad4-Reduced Human Gastric Carcinomas Is Associated with a Poor Patient Outcome
Clin. Cancer Res., October 15, 2004; 10(20): 6938 - 6945.
[Abstract] [Full Text] [PDF]

Home page
 Exp. Biol. Med.Home page
T. P. Kenny, C. L. Keen, P. Jones, H.-J. Kung, H. H. Schmitz, and M. E. Gershwin
Cocoa Procyanidins Inhibit Proliferation and Angiogenic Signals in Human Dermal Microvascular Endothelial Cells Following Stimulation by Low-Level H2O2
Experimental Biology and Medicine, September 1, 2004; 229(8): 765 - 771.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
S. K. Rabindran, C. M. Discafani, E. C. Rosfjord, M. Baxter, M. B. Floyd, J. Golas, W. A. Hallett, B. D. Johnson, R. Nilakantan, E. Overbeek, et al.
Antitumor Activity of HKI-272, an Orally Active, Irreversible Inhibitor of the HER-2 Tyrosine Kinase
Cancer Res., June 1, 2004; 64(11): 3958 - 3965.
[Abstract] [Full Text] [PDF]

Home page
 Vet PatholHome page
A. F. Flint, L. U'Ren, M. E. Legare, S. J. Withrow, W. Dernell, and W. H. Hanneman
Overexpression of the erbB-2 Proto-oncogene in Canine Osteosarcoma Cell Lines and Tumors
Vet. Pathol., May 1, 2004; 41(3): 291 - 296.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
I. B. Schiffer, S. Gebhard, C. K. Heimerdinger, A. Heling, J. Hast, U. Wollscheid, B. Seliger, B. Tanner, S. Gilbert, T. Beckers, et al.
Switching Off HER-2/neu in a Tetracycline-Controlled Mouse Tumor Model Leads to Apoptosis and Tumor-Size-Dependent Remission
Cancer Res., November 1, 2003; 63(21): 7221 - 7231.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
M. L. Disis, N. Scholler, A. Dahlin, J. Pullman, K. L. Knutson, K.-E. Hellstrom, and I. Hellstrom
Plasmid-based vaccines encoding rat neu and immune stimulatory molecules can elicit rat neu-specific immunity
Mol. Cancer Ther., October 1, 2003; 2(10): 995 - 1002.
[Abstract] [Full Text]

Home page
 J. Biol. Chem.Home page
V. P. Ramsauer, C. A. C. Carraway, P. J. I. Salas, and K. L. Carraway
Muc4/Sialomucin Complex, the Intramembrane ErbB2 Ligand, Translocates ErbB2 to the Apical Surface in Polarized Epithelial Cells
J. Biol. Chem., August 8, 2003; 278(32): 30142 - 30147.
[Abstract] [Full Text] [PDF]

Home page
 Mol Cancer ResHome page
J. Walker-Daniels, D. J. Riese II, and M. S. Kinch
c-Cbl-Dependent EphA2 Protein Degradation Is Induced by Ligand Binding
Mol. Cancer Res., November 1, 2002; 1(1): 79 - 87.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
A. H. Talukder, R. Bagheri-Yarmand, R. R. E. Williams, J. Ragoussis, R. Kumar, and A. Raz
Antihuman Epidermal Growth Factor Receptor 2 Antibody Herceptin Inhibits Autocrine Motility Factor (AMF) Expression and Potentiates Antitumor Effects of AMF Inhibitors
Clin. Cancer Res., October 1, 2002; 8(10): 3285 - 3289.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
A. Berezov, J. Chen, Q. Liu, H.-T. Zhang, M. I. Greene, and R. Murali
Disabling Receptor Ensembles with Rationally Design