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Signal Transduction: Multiple Pathways, Multiple Options for Therapy

Ludwig Institute for Cancer Research, Biomedical Center, Uppsala, Sweden

Key Words. Growth factor • Cytokine • Receptor • Kinase • Signal transduction • Antagonist

Carl-Henrik Heldin, Ph.D., Ludwig Institute for Cancer Research, Box 595, Biomedical Center, S-751 24 Uppsala, Sweden. Telephone: 46-18-160401; Fax: 46-18-160420; e-mail: C-H.Heldin{at}LICR.uu.se

	Abstract

Top Abstract Receptors for Signaling... Activation of Receptors by... Modular Signal Transduction... Intracellular Signaling Pathways Control Mechanisms Signal Transduction Agonists in... Signal Transduction Antagonists... Perspectives Acknowledgements References

 
Many aspects of cell behavior, such as growth, motility, differentiation, and apoptosis, are regulated by signals cells receive from their environment. Such signals are important, e.g., during embryonal development, wound healing, hematopoiesis, and in the regulation of the immune response, and may come from interactions with other cells or components of the extracellular matrix, or from binding of soluble signaling molecules to specific receptors at the cell membrane. Hereby different signaling pathways are initiated inside the cell. Perturbations of such signaling pathways are seen in several types of diseases, e.g., cancer, inflammatory conditions, and atherosclerosis. Thus, antagonists of several signaling pathways have potential clinical utility. Several such compounds are currently used or are in clinical trials; others are currently being analyzed in animal models.

	RECEPTORS FOR SIGNALING MOLECULES

Top Abstract Receptors for Signaling... Activation of Receptors by... Modular Signal Transduction... Intracellular Signaling Pathways Control Mechanisms Signal Transduction Agonists in... Signal Transduction Antagonists... Perspectives Acknowledgements References

 
Cells receive information from their environment affecting their growth, motility, differentiation, and apoptosis, which are important events during the development of the embryo, as well as in the adult during wound healing, hematopoiesis, and in the regulation of the immune system. Signals come from direct interaction of the cell with other cells and with the extracellular matrix, as well as from soluble growth factors or cytokines; more than 100 such factors, organized in families of structurally related molecules, are known. A number of different types of cell surface receptors for signaling molecules have recently been identified, which after activation by ligand binding, initiate a number of intracellular pathways leading to various cellular responses [1, 2].

Soluble signaling molecules often bind to receptors associated with kinase activity. Many so-called growth factors bind to receptors which contain an intrinsic tyrosine kinase domain [3], whereas many so-called cytokines bind to receptors devoid of kinase domain but which bind to intracellular kinases of the Jak family [4]. In these cases, ligand binding induces receptor dimerization or oligomerization resulting in tyrosine phosphorylation of the receptors and activation of specific signaling pathways leading, e.g., to cell growth, migration, or prevention of apoptosis [5].

T- and B-cell antigen receptors, which recognize different forms of antigens at the surface of antigen-presenting cells, also form oligomers after ligand binding. Within such complexes, "antigen recognition activation motifs" are phosphorylated on specific tyrosine residues leading to binding and activation of tyrosine kinases of the ZAP-70/Syk family and initiation of intracellular signal transduction [6].

Focal adhesions are sites where integrins mediate contacts between the extracellular matrix molecules and the intracellular cytoskeleton. At such sites, cytoplasmic tyrosine kinases, e.g., of the Src family, are activated resulting in growth stimulatory, antiapoptotic, and migratory signals [7].

In contrast, members of the transforming growth factor-ß (TGF-ß) family, which affect differentiation of cells, e.g., during embryonal development, and most often inhibit their growth, bind to receptors with intrinsic serine/threonine kinase activity [8, 9]. Ligand binding induces the formation of a heterotetrameric complex of two copies each of two different types of serine/threonine kinase receptors.

There are also receptors for signaling molecules that are not associated with kinase activity. For instance, the trimeric members of the tumor necrosis factor (TNF) family bind to and trimerize receptors which are devoid of kinase activity. Many of these receptors have conserved motifs in their intracellular parts, referred to as death domains; these mediate contact with adaptor molecules which bind components in the proteolytic cascade leading to apoptosis [10].

There are also receptors that span the plasma membrane several times. The seven transmembrane-spanning receptors, which couple to G proteins, bind chemokines, peptides, lipids, and other low-molecular-weight ligands, and are the largest gene product family known [11, 12]. Members of the Wnt [13] and hedgehog [14] families of developmental regulators also bind to receptors which span the membrane several times. Moreover, ligand-gated ion channels and ion pumps, which have important roles in signal transduction in the central nervous system and in muscle contraction, have several transmembrane domains.

	ACTIVATION OF RECEPTORS BY OLIGOMERIZATION

Top Abstract Receptors for Signaling... Activation of Receptors by... Modular Signal Transduction... Intracellular Signaling Pathways Control Mechanisms Signal Transduction Agonists in... Signal Transduction Antagonists... Perspectives Acknowledgements References

 
Ligand-induced dimerization or oligomerization appears to be a unifying concept for activation of receptors that span the plasma membrane only once [5]. There are, however, many variations on the theme (Fig. 1).

View larger version (22K): [in this window] [in a new window]   Figure 1. Schematic illustration of three different receptor types and their downstream pathways. The receptors are drawn to indicate that ligand binding induces dimerization or oligomerization. Examples of crosstalk between different pathways are indicated.

Recent observations have illustrated that oligomerization may not be sufficient to activate kinase-associated receptors. The insulin receptor, which is a disulfide-bonded dimer, is an obvious example [18], but the erythropoietin receptor has also been shown to occur as a preformed dimer [19]. In these cases, ligand binding is likely to change the conformation of the dimers, e.g., placing the receptors in the right orientation leading to their activation [20].

Whereas ligand-induced oligomerization appears to be a key event for initiation of signaling via kinase-associated receptors, there is evidence that subsequent inhibition of phosphatases is important for the maintenance of the signal, at least from tyrosine kinase receptors [21-23].

Ligand-induced oligomerization of kinase-associated receptors leads to juxtaposition of the kinase domains so that they can phosphorylate each other [5]. However, TNF receptors which are devoid of kinase activity are also activated by oligomerization. In this case, the receptor binds the initiator caspases in the proteolytic cascade leading to cell death; since caspases are activated by proteolytic cleavage, it is likely that receptor oligomerization brings the initiator caspases sufficiently close to each other for reciprocal proteolytic activation to occur [10].

	MODULAR SIGNAL TRANSDUCTION MOLECULES

Top Abstract Receptors for Signaling... Activation of Receptors by... Modular Signal Transduction... Intracellular Signaling Pathways Control Mechanisms Signal Transduction Agonists in... Signal Transduction Antagonists... Perspectives Acknowledgements References

 
An important lesson from recent years' work is that transduction of signals through the cytoplasm involves physical interactions and formation of stable complexes of different signal transduction molecules. Such interactions are mediated by conserved domains present in the signaling molecules; certain domains recognize phosphorylated tyrosine residues in defined environments (SH2 and PTB domains); others recognize proline-rich sequences (SH3 and WW domains), C-terminal valine or leucine residues (PDZ domains), or phospholipids (PH domains) [24].

Since many plasma membrane receptors undergo tyrosine phosphorylation in conjunction with activation, signaling pathways are often initiated by the binding of SH2- or PTB-domain-containing molecules to the receptors. Specificity is achieved through the fact that different SH2 and PTB domains recognize phosphorylated tyrosines in different environments. Moreover, the recruitment of signaling molecules to the inner leaflet of the plasma membrane via the binding of phospholipids by PH domains is also important for efficient interaction between SH2- or PTB-domain-containing signaling molecules and phosphorylated receptors [25].

There are, in principle, two different kinds of molecules in intracellular signaling pathways. Some signaling molecules are equipped with enzymatic activity, such as protein kinase, lipid kinase or phospholipase; induction of these activities or changes in their subcellular localization initiate signaling. The other type of signaling molecules lacks intrinsic enzymatic activity and acts as adaptor molecules which bring other signaling molecules together. Thus, signaling molecules are modular and contain domains mediating interaction with other signaling molecules, and sometimes, domains containing enzymatic activity [24].

	INTRACELLULAR SIGNALING PATHWAYS

Top Abstract Receptors for Signaling... Activation of Receptors by... Modular Signal Transduction... Intracellular Signaling Pathways Control Mechanisms Signal Transduction Agonists in... Signal Transduction Antagonists... Perspectives Acknowledgements References

 
Each one of the SH2- or PTP-domain-containing molecules that binds to phosphorylated receptors or receptor-associated molecules potentially initiates a signaling pathway (Fig. 1). An important pathway involves the GTP binding protein Ras, which activates the Erk MAP kinase cascade leading to cell proliferation [26]. Ras is farnesylated and resides at the inner leaflet of the cell membrane [27]; it is activated by the nucleotide exchange molecule Sos1, which forms a complex with the adaptor molecule Grb2. Through its SH2 domain, Grb2 mediates binding to phosphorylated tyrosine residues in receptors or receptor-associated molecules. Activated Ras binds to and activates the MAP kinase kinase kinase Raf, which then phosphorylates and activates the MAP kinase kinase MEK, which finally phosphorylates and activates the MAP kinase Erk; Erk is then translocated into the nucleus where it regulates the activity of certain transcription factors through phosphorylation [28].

Membrane phospholipids are involved in at least two signaling pathways: phosphatidylinositol-3'-kinase (PI3-kinase) phosphorylates phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P₂) to PtdIns-3,4,5,-P₃ which activates the serine/threonine kinase Akt and the GTP binding protein Rac, promoting cell survival, and actin reorganization and cell migration, respectively [29]. PI3-kinase consists of an SH2-domain-containing regulatory subunit which binds to activated receptors and a catalytic subunit which is activated in conjunction with this binding. The same substrate, PtdIns-4,5-P₂ is also used by another signaling molecule, phospholipase C- (PLC-), resulting in diacylglycerol and inositol-1,4,5-trisphosphate, which activates members of the protein kinase C family, and mobilizes Ca²⁺ from intracellular stores, respectively [30]. After the SH2-domain-containing PLC- molecule has bound to an activated receptor, it is phosphorylated on a specific tyrosine residue, which activates its catalytic activity [31].

Members of the Src family of tyrosine kinases are important for mitogenic signaling downstream of, e.g., tyrosine kinase receptors and integrins [7, 32]. Src contains an SH2 domain and is activated by the binding of this domain to a phosphorylated tyrosine residue, which—together with dephosphorylation —relieves an intramolecular inhibitory interaction between the SH2 domain and a C-terminal phosphorylated tyrosine residue. Src activation induces, via unknown intermediaries, expression of the transcription factor c-Myc [33].

Stat molecules are important signaling molecules downstream of cytokine receptors [34]. Each Stat molecule contains an SH2 domain with which it binds to phosphorylated tyrosine residues in receptors. After tyrosine phosphorylation by Jak kinases, the SH2 domains of Stat molecules mediate dimerization, whereafter the Stat complexes are translocated to the nucleus, where they regulate the transcription of specific genes.

Smad molecules act downstream of serine/threonine kinase receptors in a manner analogous to that of Stats. Receptor-activated Smads (R-Smads) are phosphorylated by type I serine/threonine receptors in -SXS motifs in their extreme C-termini. This triggers the interaction with common-mediator Smad4; the Smad complexes are then translocated into the nucleus where, in cooperation with other transcription factors, they regulate specific genes [8, 9].

	CONTROL MECHANISMS

Top Abstract Receptors for Signaling... Activation of Receptors by... Modular Signal Transduction... Intracellular Signaling Pathways Control Mechanisms Signal Transduction Agonists in... Signal Transduction Antagonists... Perspectives Acknowledgements References

 
Given that decisions whether to proliferate or die are of utmost importance for a cell, it is not surprising that the intracellular pathways discussed above are carefully controlled by inhibitory feedback mechanisms. The mechanisms controlling signaling by members of the TGF-ß family have been particularly well characterized; controlling mechanisms have been identified at almost all possible levels, including interference of ligand binding to receptors, receptor activation, and activation and function of Smad molecules [35]. One interesting example is the induction after ligand binding of a subfamily of Smads with inhibitory action. Analogously, inhibitory CIS/SOCS molecules are induced after activation of cytokine receptors [36, 37]. One important mechanism for the inhibitory effects of members of the Smad and CIS/SOCS family was recently unraveled; these molecules bind ubiquitin ligases and target them to specific signaling molecules [38-41]. Ubiquitin-mediated degradation of signaling molecules is an important control mechanism for signaling [42]. Through a specific recognition machinery, certain signaling molecules are ubiquitinated and thereby marked for degradation in proteasomes; the number of signaling molecules is thereby kept at an appropriate level. Moreover, in several cases, signaling is ended by ubiquitin-mediated degradation of activated signaling molecules. For example, the ubiquitin ligase Cbl interacts with and downregulates certain tyrosine kinase receptors [43, 44].

Another mechanism for control of signal transduction is induction at the receptor level of an inhibitory signal in parallel to the stimulatory one. One example is activation of Ras, which occurs by the recruitment of the nucleotide exchange molecule Sos1 in complex with the adaptor molecule Grb2 to activated receptors. Certain receptors, like the PDGF ß-receptor, have the ability to also bind Ras GTPase activating protein (GAP), which exerts a negative effect on Ras, i.e., converting active Ras•GTP to inactive Ras•GDP [15] (Fig. 1). The amount of Ras activation will thus be dependent on the balance between binding of Grb2/Sos1 and RasGAP to the receptor, which in turn is dependent on the stoichiometry of phosphorylation of different tyrosine residues. Signaling from kinase-associated receptors is also controlled by dephosphorylation by specific phosphatases. Examples include the cytoplasmic tyrosine phosphatase 1B which controls the insulin receptor with some selectivity [45], the SH2-domain-containing tyrosine phosphatase SHP-1, which controls the erythropoietin receptor [46], SHP-2, which controls the PDGF receptor [47], and the transmembrane tyrosine phosphatase CD45 which controls Jaks activated by cytokine receptors [48].

A striking feature of intracellular signal transduction is that extensive crosstalk occurs between different signaling pathways (Fig. 1). Thus, intracellular signaling occurs through a network of interacting signaling components, rather than through a number of parallel pathways [49-51]. One example of crosstalk is between PI3-kinase and Ras, major signaling components downstream of several receptor types, which interact physically and activate each other [52, 53]. Moreover, the typical pathways activated by tyrosine kinase receptors, PLC-, PI3-kinase, and Src, are also activated by cytokine receptors or by integrins; on the other hand, Stat molecules which are typically activated by cytokine receptors are also activated by tyrosine kinase receptors. There are also examples of inactivating crosstalk between signaling pathways. For instance, Erk MAP kinase, which is activated downstream of kinase-associated receptors, can phosphorylate Smad molecules and thereby inhibit signaling downstream of serine/threonine kinase receptors [54]. Protein kinase C [55] and Ca²⁺-calmodulin-dependent activated kinase [56], which are activated downstream of PLC-, can also phosphorylate Smads in inhibitory manners (Fig. 1).

	SIGNAL TRANSDUCTION AGONISTS IN THERAPY

Top Abstract Receptors for Signaling... Activation of Receptors by... Modular Signal Transduction... Intracellular Signaling Pathways Control Mechanisms Signal Transduction Agonists in... Signal Transduction Antagonists... Perspectives Acknowledgements References

 
Insulin has been used for treatment of diabetes for more than 70 years. The ability to make large quantities of recombinant proteins has opened up the possibility to also use other growth factors and cytokines clinically. One example is erythropoietin, which is used successfully for treatment of anemia [57]. Other factors, such as PDGF, are used to stimulate wound healing [58]. Yet other factors have shown promising results in animal models and are currently in clinical trials, for example, VEGF for stimulation of re-endothelialization and blood flow [59, 60].

In view of the expense in producing and the difficulty in administering proteins, low-molecular-weight activators of certain receptors have also been developed, such as insulinomimetic agents which activate the tyrosine kinase receptor for insulin [61], as well as compounds which activate the cytokine receptors for G-CSF [62] and erythropoietin [63, 64].

An alternative way to enhance specific signaling pathways is to inhibit negative regulators. Thus, specific phosphatases, ubiquitin ligases, and other components of negative modulatory mechanisms are interesting targets for drug discovery.

	SIGNAL TRANSDUCTION ANTAGONISTS IN THERAPY

Top Abstract Receptors for Signaling... Activation of Receptors by... Modular Signal Transduction... Intracellular Signaling Pathways Control Mechanisms Signal Transduction Agonists in... Signal Transduction Antagonists... Perspectives Acknowledgements References

 
Since overactivity of growth factors or cytokines is implicated in a number of serious disorders, antagonists of their action are highly warranted. Such antagonists are being evaluated for the treatment of cancer [65], as well as for the treatment of atherosclerosis and fibrotic conditions. The types of inhibitors that have been developed for clinical use include antisense oligonucleotides to specifically lower the amount of a particular signal transduction molecule, molecules that sequester ligands or prevent ligands from binding to their receptors, and low-molecular-weight inhibitors of enzymes in signal transduction pathways (Table 1). The development of kinase inhibitors has been particularly successful, and a number of fairly selective inhibitors of tyrosine kinases as well as serine/threonine kinases are now available [66].

HER2, a member of the EGF receptor family, is amplified or upregulated in 25%-30% of human breast cancers [67]. No ligand for HER2 has yet been identified, but HER2 is known to have an important role in heterodimers with other members of the EGF receptor family [16, 17]. A monoclonal antibody (trastuzumab) against the extracellular domain has been developed at Genentech (South San Francisco, CA; http://www.gene.com) and is now used for treatment of breast cancer [68]. Trastuzumab has also been used in combination with classical chemotherapy [69]. Such combination treatments of modern, specific signal transduction antagonists and classical treatment protocols are being tried in many contexts to improve efficiency. Monoclonal antibodies have also been developed against the EGF receptor [70, 71]; they have been used together with chemotherapy or radiotherapy in head and neck cancers, with promising results. Low-molecular-weight kinase inhibitors have also been developed against the EGF receptor; of particular interest is an irreversible inhibitor, PD-168393, which binds specifically to a cysteine residue close to the ATP binding site [72]. Since the EGF receptor gene is often amplified in glioblastoma, this disease is an interesting target for EGF receptor kinase inhibitors. The PDGF receptor is often overactive in glioblastoma, and treatment with inhibitors of this kinase, e.g., SU-101 [73], has also been tried.

Since the insulin-like growth factor-I (IGF-I) receptor induces particularly powerful antiapoptotic signals [74], IGF-I receptor antagonists may be of general utility in tumor treatment. Consistent with this notion, an antisense oligonucleotide against the IGF-I receptor was found to induce tumor apoptosis [75].

Targeting tumor angiogenesis offers a general mechanism to inhibit the growth of solid tumors. Angiostatin and endostatin are fragments of plasmin and collagen XVIII, respectively, which have angiostatic effects [76, 77]. Moreover, monoclonal antibodies [78], the soluble extracellular domain of VEGF receptors [79, 80], and several low-molecular-weight inhibitors of vascular endothelial growth factor (VEGF) receptor kinase [81, 82] have been developed and have shown promising results in model systems.

Chronic myeloid leukemia is caused by the fusion of Bcr with the Abl tyrosine kinase. An inhibitor of this kinase, STI571, has shown promising effects in clinical trials [83]. STI571 also inhibits the receptors for stem cell factor and PDGF and is therefore potentially useful in lung cancer, where overactivity of the stem cell factor is common [84]; in dermatofibrosarcoma protuberance, which is characterized by a fusion between the genes for PDGF-B and collagen IA1 resulting in autocrine stimulation by a PDGF-like growth factor [85]; and in myelomonocytic leukemia, which is characterized by a fusion between the genes for the transcription factor Tel and the ß-receptor for PDGF resulting in a constitutive activation of the receptor kinase [86]. Inhibition of the PDGF receptor kinase also leads to a lowering of the tumor interstitial tissue fluid pressure, which is often elevated in tumors, and thereby improves the uptake of drugs [87]. This effect, which is mediated via inhibition of PDGF receptors in the stromal compartment of tumors, makes PDGF receptor kinase inhibition potentially useful to potentiate chemotherapy of solid tumors. PDGF antagonists are also potentially useful in the treatment of atherosclerotic lesions. Thus, antibodies [88], a Selex DNA aptamer with the ability to sequester PDGF and prevent its binding to receptors [89], or the receptor kinase antagonist AG1295 [90], were found to inhibit intimal hyperplasia approximately 50% in different animal models.

Since Ras is commonly mutated and activated in human malignancies, quite an effort has gone into the development of Ras inhibitors. An antisense oligonucleotide (ISIS-2503) against Ha-Ras showed antitumor activity in mouse xenograft tumor models and is now in clinical trials [91]. Another approach to inhibit Ras function is to inhibit its membrane association through inhibition of its farnesylation. Several farnesyltransferase inhibitors have been developed [92], and are now being evaluated in clinical trials. One worry with these compounds is side effects, since many different proteins are dependent on farnesylation for their function.

Low-molecular-weight inhibitors and other antagonists have also been developed against several intracellular serine/threonine kinase inhibitors, such as Raf [93], MEK [94] and PKC [95]; their clinical usefulness in tumor treatment is now being evaluated. Inhibitors of lipid kinases such as PI3'-kinase, are also potentially useful in tumor treatment.

	PERSPECTIVES

Top Abstract Receptors for Signaling... Activation of Receptors by... Modular Signal Transduction... Intracellular Signaling Pathways Control Mechanisms Signal Transduction Agonists in... Signal Transduction Antagonists... Perspectives Acknowledgements References

 
Agonists and antagonists for signal transduction pathways are likely to be valuable drugs for the future treatment of various disorders. Using high-throughput screens combined with combinational chemistry and rational design, several low-molecular-weight antagonists for kinases or other enzymes, have been developed. Availability of the three-dimensional structure of the enzyme to be targeted helps in the refinement of the structures to give higher specificity. Another mode of antagonism is to inhibit the interaction between components in signaling pathways. Since these interactions occur between fairly large and flat epitopes, the development of low-molecular-weight inhibitors is less straightforward; it remains to be explored how useful this approach will be.

Since intracellular signaling occurs through a signaling network rather than through linear signaling pathways, it is not obvious whether it is a greater advantage to inhibit signaling at the cell membrane or farther down in the signaling network/pathways. Using antagonists which sequester ligands or bind to the extracellular part of a receptor and thereby prevent ligand binding, or low-molecular-weight inhibitors of the kinase activity of receptor-associated kinases, all signals downstream of a particular receptor are inhibited. Alternatively, when downstream components are targeted, it is possible to inhibit certain signals from a particular receptor but retain others, which in certain situations could be advantageous. For instance, for the treatment of fibrotic conditions, it is desirable to inhibit the effect on matrix accumulation after TGF-ß stimulation but retain the growth inhibitory activity of TGF-ß so as not to promote tumor cell growth. Much work remains before the optimal types of signal transduction inhibitors for various diseases can be designed.

	Acknowledgements

Top Abstract Receptors for Signaling... Activation of Receptors by... Modular Signal Transduction... Intracellular Signaling Pathways Control Mechanisms Signal Transduction Agonists in... Signal Transduction Antagonists... Perspectives Acknowledgements References

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Top Abstract Receptors for Signaling... Activation of Receptors by... Modular Signal Transduction... Intracellular Signaling Pathways Control Mechanisms Signal Transduction Agonists in... Signal Transduction Antagonists... Perspectives Acknowledgements References

 

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