Bntii* MiMcai BulUlm (1991) Vol 47, No. 1, pp 99-115 © The Bntiih Council 1991

Signal transduction D Hollywood Imperial Cancer Research Fund, Molecular Oncology Group, Hammersmith Hospital, Royal Postgraduate Medical School, London, UK

Ordered cell proliferation relies on a complex interplay between diverse cell types, interstitial stroma and organ vasculature. At a cellular level the response to growth stimuli is dependent on the bidirectional exchange of information between the cell membrane and nucleus. Specific regulatory molecules enable the transfer of growth signals and constitute the signal transduction pathways. In malignant disease deregulation of growth regulatory pathways is believed to contribute to the characteristic features of neoplasia, unrestricted cell proliferation, direct invasion of surrounding tissues and the formation of distant metastases. Many proto-oncogenes and oncogenes encode proteins that are strongly suspected to function in aberrant signal transduction (Table 1).

The 'multiple signal' model proposes that a number of signal transduction pathways exist, each contributing to the eventual mitogenic response.1 Some elements of the signalling apparatus are not essential for transduction of the growth stimulus, their Table 1 Membrane-associated and cytoplasmic oncogenes Membrane associated guanlne nucleotide binding proteins c-H-roi, c-K-rm, N-raj Cytoplasmic tyroslne klnases c-src-1, c-src-2, c-fyn, c-yes c-abl, c-fes, c-sea, trk, tck

Cytoplasmic serine-threonine kinases c-rafl, c-mos, pirn 1




presence fulfilling a regulatory role rather than an obligatory requirement. A degree of crosstalk between the pathways is believed to exist. Components of the pathways are often considered in heirarchical terms relating both their cellular location and functional role, for example growth factors, growth factor receptors, cytoplasmic second messengers and transcription factors. The remit of this chapter is those intermediary elements of the signal transduction pathway that operate following growth factor activation and precede the production of factors directly regulating gene expression.

MEMBRANE EVENTS Models of neoplastic existence include cellular systems dependent on the production of autocrine and paracrine growth factors.2 Transfer of such an extracellular growth stimulus to the intracellular second messengers is relayed via a range of 'receptors' sited at the cell membrane (Fig. 1): (a) Transmembrane protein tyrosine kinases. (b) Membrane ion channels. (c) Membrane associated guanine nucleotide binding (G) proteins. In addition certain cytoplasmic and nuclear receptors bind specific lipophilic growth factors exemplified by steroid hormones and retinoic acid.3 The resultant ligand receptor complex migrates to the nucleus to interact with specific DNA sites controlling gene regulation thereby bypassing the membrane initiated signal transduction components. Although there are a great number of extracellular growth signals only a limited number of second messengers are employed. Three intracellular growth regulatory signalling pathways are recognized: substrate phosphorylation by transmembrane receptor tyrosine kinases, the phosphatidylinositol-calcium cascade, and the cyclic AMP (cAMP) system. Major determinants of cell specificity to growth stimuli reside both at the cell membrane through the expression of highly specific receptors and at the nuclear level through sequence specific DNA binding sites regulating gene expression.4






IP3 I Ca2-





lAdenylate I /cyclase



Fig. 1 Schematic representation of the signal transduction pathways. Hatched boxes enclose the phosphatidylinositol and cyclic AMP pathways. Abbreviations: Na/H antiport; PTPase: protein tyrosine phosphatases; Ca2 + : calcium; RTK: transmembrane receptor tyrosine kinases; PLC: phospholipasc C; PLD: phospholipase D; PLA2: phospholipase A2; PC: phosphocholine; PIP2: phosphatidylinositol 4,5-biphosphate; Gs/Gi: stimulatory/inhibitory Gprotein complcxpgl: phosphatidylinositol 3-kinase; IP3: inositol 1,4,5-triphosphate; DAG: 1,2 diacylglycerol; PKC: protein kinase C; PKA: protein kinase A

RECEPTOR TYROSINE KINASES Four classes of transmembrane protein tyrosine kinase receptor are recognized each containing high affinity sites for specific extracellular molecules. Ligand-receptor interaction results in receptor oligomerization, activation of the cytoplasmic tyrosine kinase domain and signal transfer.56 A recently proposed model suggests that the tyrosine kinase domain of the transmembrane receptors may exist in association with certain regulatory molecules forming a 'signal transduction particle'. 78 Receptor activation through ligand binding alters the composition of the 'signal particle' pre-



senting an active kinase domain for phosphorylation of a specific substrate. An alternative model proposes that instead of a single multicomponent complex unifying all the regulatory factors, several forms of receptor-complex exist each containing a lesser number of the regulatory proteins.10 Transduction of the growth stimulus from the receptor complex to the cytoplasmic second messengers is absolutely dependant on a functional kinase domain. Kinase inactivation blocks the production of downstream signalling components—for example inositol phosphate formation, intracellular calcium release and expression of the early immediate genes c-myc and c-fos. Tyrosine phosphorylation of target proteins located at the cell membrane and cytoplasm initiates a number of post-receptor signal transduction cascades. Several proteins are known to be phosphorylated following kinase action and are believed to be downstream elements of the signal transduction pathways (Fig. 1). Substrates include phospholipase Cy (PLC), 11 GTPase activating protein (GAP),12 p81 a phosphatidylinositol 3-kinase (PI-3 kinase),13 and the c-raf protooncogene product.14 Phosphorylation of PLCy results in the generation of inositol 1,4,5-triphosphate (IP3) and 1,2 diacylglycerol (DAG). In turn DAG and IP3induced calcium release collectively stimulate protein kinase C (PKC), a serine-threonine kinase. Following PKC activation the next in line signalling elements are unknown. Signal limitation following ras activation may be dependent on phosphorylation of tyrosine residues on the GTPase activating protein (GAP).12 Recently an interaction between membrane tyrosine kinases and cytoplasmic src tyrosine kinases has been demonstrated.10 PDGF receptor activation is followed by phosphorylation of src family members (pp60src, p59fyn, p62yes) and an increase in src kinase activity. Whether this represents src autophosphorylatdon or phosphorylation by the PDGF receptor remains unresolved. Activation is paralleled by transient complex formation between the PDGF receptor, p81 and the src tyrosine kinase suggesting a linkage between receptor activation, inositol phosphate metabolism and intracellular tyrosine kinase action. Additional signal transduction elements may be involved, preceding 'early immediate gene' induction and DNA synthesis, however these remain unknown. Transfer of a growth signal following membrane receptor activation involves the stimulation of one or more pathways. It is also clear that the requirements for signal transduction are not rigid and variations in the second messenger response exist depending



on the particular ligand-receptor complex and the specific cell type. For example following PDGF stimulation of NIH 3T3 cells transfected with bovine PLC y , calcium release does not appear to be dependant on PLCT-induced IP3 production. The absence of correlation between PI production and calcium release may be due to desensitization of the IP3 receptor, the extrusion of intracellular calcium or the internal sequestration of IP3. 9 In addition other inositol phosphate metabolites may play a more direct role in calcium release. In this setting the phosphidylinositol pathway may not be essential for the mitogenic response. PROTEIN TYROSINE PHOSPHATASES Substrate tyrosine phosphorylation may also depend on the action of protein tyrosine phosphatases (PTPases). At present the role of this family of enzymes in both signal transduction and malignant transformation is unclear. Possible actions include direct activation of signalling pathways or the limitation of signal propagation by protein tyrosine kinases.15 Four members of the PTPase family are recognized; PTPase IB, T-cell PTPase, CD45, and leukocyte common antigen related protein (LAR). Structural considerations suggest PTPase IB and T-cell PTPase are cytoplasmic although an extended C-terminus on T-cell PTPase may allow localization to specific intracellular compartments. Some gross comparisons exist between CD45, LAR and membrane tyrosine kinases (O- and N-glycosylated extracellular domains, hydrophobic transmembrane segment, and a cytoplasmic catalytic domain) suggesting that the PTPases are transmembrane molecules with possible ligand binding properties. A ligand binding capacity raises other possibilities given our present knowledge of PTPase expression. Several isoforms of CD45 exist resulting from the differential expression of sequences encoding the putative extracellular 'receptor' domains, thus cell specific expression of different isoforms may tailor PTPase activity to specific ligands. Moreover some cells express several isoforms creating the possibility of changes in ligand specificity at different points in a cell's lifespan.15 Clarification of PTPase action will require the identification of both substrate and ligand. Putative substrates include the cytoskeletal protein fodrin and the lymphocyte cell surface antigens CD3 and CD4. The interaction of CD45 with CD3 and CD4 suggests a variable role in signal transduction. Crosslinking of



CD3 and CD45 inhibits inositol phosphate formation and calcium release. In contrast crosslinking of CD4 and CD45 enhances calcium release possibly through dephosphorylation and activation of the lymphocyte specific tyrosine kinase p56lck.16 LAR shows homology with neural cell adhesion molecules (NCAM), a family of proteins involved in the cell-cell interactions of growth and morphogenesis.17 Interaction and activation of LAR molecules on different cells may play a role in contact inhibition through a dampening effect on receptor tyrosine kinase activity. Thus membrane PTPase activity may inhibit or enhance signal transduction depending on the other membrane proteins encountered. MEMBRANE ION CHANNELS Exposure of a wide range of cells including Swiss 3T3 cells to growth factors results in rapid cytoplasmic alkalinization following Na + entry and H + exit at the amiloride sensitive Na + /H + antiport (Fig. 1). The resultant increase in intracellular Na + enhances Na + /K + pump activity thereby elevating intracellular K + and returning Na + to its original level. Artificial limitation of Na + influx to that of quiescent cells diminishes DNA synthesis, suggesting Na + entry is a prerequisite for cellular proliferation. The role of ion exchange is controversial. Supporters of a direct mitogenic role argue that growth factors alter the 'Na + cycle' and the resultant alkalinization and increased intracellular K + both act directly to modulate signal transduction pathways.1'18 The counter argument disputes the proposed primary role indicating that few enzymes show significant alteration in activity with the observed order of pH change (0.21 units) and K + increase. Cytoplasmic alkalinization is seen as a secondary response to the increased metabolic rate accompanying DNA replication and cell division. The increase in pH limits the acidotic tendancy accompanying increased glycolysis, DNA replication and cell division, rather than directly initiating growth regulatory pathways.19 G-PROTEINS G-proteins facilitate signal transfer between specific membrane receptors and second messenger generating systems located at the cytoplasmic surface of the cell membrane. Ligand-receptor



binding results in the activation of specific G-proteins and transfer of the signal to several second messenger systems including those recognised to have a role in growth regulation: adenylate cyclase activity resulting in cAMP production, and phospholipase C induction of phosphatidoinositol (PI) metabolism. At present no aberrant G protein has been clearly demonstrated to have a primary role in the evolution of malignant cells. However their action may be required to maintain the integrity of growth signalling pathways (cAMP, PI systems) and to support other metabolic processes not directly involved in neoplastic transformation. In addition, the recognition of similarities between Gs and the ras protein has suggested possible substrates downstream of ras activation. cAMP pathway The interaction of G-proteins with adenylate cyclase provides an example of G-protein action (Fig. 2). Two G-proteins, a stimulatory (Gs) and inhibitory (Gi) protein, are involved in the control of adenylate cyclase. The Gs protein consists of three subunits a, P and y. In the inactive state guanosine diphosphate (GDP) is bound to the Gs a subunit. Ligand receptor interaction results in GTP: GDP exchange followed by dissociation of the a subunit from the p and y subunits. The Gs a-GTP complex activates adenylate cyclase, and hydrolysis of GTP to GDP returns Gs to the ground state with reassociatdon of the a, P and y subunits. In return the enhancement of adenylate cyclase activity elevates cAMP levels activating a range of cAMP-dependent protein kinases (PKA). PKA action results in the phosphorylation of specific substrates. The identity of the target proteins remains unknown but they appear separate from those phosphorylated by receptor/non-receptor tyrosine kinases. Certain genes contain as-acting promoter elements that mediate induction by cAMP.20 The cAMP response elements (CRE) bind a family of related transcription factors known as the cAMP response element binding proteins (CREB) or activating transcription factors (ATF). The substrates of PKA and other cAMP signal transduction compounds eventually result in CREB activation and induction of cAMP-dependent gene expression. Recently heterodimerization of CREB-B1 with proteins of another transcription factor family (jUN protein) has been described.21 This provides







dependant protein klnases


Fig. 2 Schematic representation of activation of the adenylate cyclasc and the cAMP pathway. The mechanism of interaction between a transmembrane receptor (eg: PDGF), intermediary G protein and adenylate cyclasc is unknown. Other factors (eg:bombesin, intcrleukin 3) lead to activation by other receptor types, a, p and y represent the stimulatory G protein (Gs) subunits



a mechanism whereby signals utilizing separate transduction pathways may unify through the production of protein complexes essential for the regulation of gene expression. Using a thryoid epithelial model the induction of cAMP, by TSH exposure or cAMP activators (cholera toxin, forskolin), resulted in non-neoplastic thyrocyte proliferation.22 Other cell systems may require the concommitant activation of cAMP independent pathways, for example coactivation of the membrane tyrosine kinases or stimulation of the phosphatidylinositol cascade. The signalling mechanisms appear to act in parallel with little crosstalk between the proximal constituents of the alternative pathways. Thus in fibroblasts the elevation of cAMP levels does not directly result in calcium release, Na + /H + exchange, cytoplasmic alkalinization or activation of PKC. The distal end of the signalling pathways show some similarities both inducing the expression of the early immediate genes (c-fos and c-jun). Thus in specific cells activation of the cAMP pathway may suffice as a positive growth signal. In others the cAMP-dependent and independent signalling pathways are both necessary, initially acting as separate transduction cascades but capable of synergistic action through the activation of similar final common pathways. DAG AND CALCIUM RELEASE Several signalling events lead to the production of the important signalling intermediary 1,2 diacylgylcerol (DAG). DAG is a key modulator of PKC, a serine-threonine kinase that may form the entry point to one of a small number of final common pathways regulating gene expression. Recently a number of pathways where phosphatidylcholine metabolism results in DAG production have been described.23 These may form alternative mechanisms for PKC activation. Thus production of DAG from membrane phospholipids may utilize both the phosphatidylinositol and phosphocholine pathways. Phosphatidylinositol pathway Signal transduction between certain receptor complexes and the phosphatidylinositol (PI) pathway is believed to involve an intermediary G-protein (Gp) and a PI specific phosphalipase C (polyphosphoinositol phosphodiesterase: PPIpde) (Figs 1 and 3). PPIpde cleaves the membrane lipid phosphatidylinositol-4,5-



Fig. 3 Activation of the protein kinase C by the phosphatidyl and phosphocholine pathways? represents a possible interaction. PIP2: phosphatidylinositol 4,5-biphosphate. DAG: 1,2 diacylglycerol; IP3: inositoll, 4, 5 triphosphatc; PLC: phospholipase C; PLD: phospholipase D; PLA2: phospholipase A2; GPC: glycerophosphocholine; G3P: glycerol 3 phosphate; PKC: protein kinase C RTK: receptor tyrosine kinase; Gp: putative phosphatidylinositol specific G protein; Ca: calcium; PPIpde: polyphosphoinositol-phosphodicsterase

biphosphate (PIP2) resulting in the production of 1,2 diacylgylcerol (DAG) and inositol-l,4,5-triphosphate (IP3). IP3 acts to mobilize intracellular calcium probably from endoplasmic reticulum stores there-by raising the intracellular calcium concentration. The presence of DAG is shortlived and in conjunction with released calcium leads to activation of key calcium dependant growth regulatory enzymes in particular protein kinase C (PKC).24-25 Phosphocholine pathway Three enzyme systems result in the production of DAG from membrane phosphocholine (PC) Figs 1 and 3):



(a) phosphatidylcholine specific phospholipase C (PLC), (b) phospholipase D (PLD), (c) phospholipase A2 (PLA2). Activation of the phosphatidylcholine specific PLC results in the catabolism of PC and the direct production of DAG. The sequential action of PLD and PA phosphorylase also generates DAG. The third route, via PLA2 activity, involves the production of several intermediate compounds including another putative signalling molecule, arachadonic acid. Unlike the phosphatidylinositol pathway the production of DAG from PhC is not accompanied by calcium release. Nevertheless DAG can activate protein kinases including protein kinase C, although this may necessitate the presence of free fatty acids following PLA2 action. DAG also acts in a positive feedback pathway enhancing PhC turnover and the production of further DAG. With this in mind a role for PhC metabolism in the maintenance of signal transduction has been proposed. In the model ligand-receptor interaction results in the transient activation of the phosphatidylinositol pathway leading to the initial calcium release, DAG production and PKC stimulation. The shortlived increase in DAG is sufficient to recruit further DAG production through positive feedback stimulation of PhC hydrolysis, thereby augmenting the early cytoplasmic signal. Thus the initial stimulation of PKC may result from transient production of phosphatidylinositol based DAG/ calcium, the signal being maintained by a more prolonged PKC activation dependent on phosphatidylcholine based production of DAG and free fatty adds. 23

RAS PROTEINS The ras family in man consists of three genes H(Harvey)-ra5, K(Kirsten)-ras, and N-ras. A wider range of ras related genes exists in other species rho, rab 1,2,3,4, RAS, RAS2 and R-ras. Each human gene encodes a 21kD membrane associated protein (p21 ras) that shows limited sequence homology to the Gs subunit. Mutant ras is the most frequently observed dominant oncogene in human malignant disease being present in 30% of all tumours.26 The function of pllras in non-neoplastic cells is unclear with roles in the control of cell growth and in the maintenance of cell differentiation being proposed. Activation of the ras oncoprotein is believed to result in the generation of a prolonged intracellular



growth signal, however both the upstream and downstream elements of the putative pathway remain unclear. Involvement in adenylate cyclase signalling is recognized in lower eukaryotic organisms, and interactions with phospholipase A2, phospholipase C, phosphatidylinositol metabolism, and transmembrane receptor activation have been suggested in man.19 The transforming ras oncogenes exist as mutant forms of the proto-oncogene. Point mutations at codons 12, 13 or 61 result in amino-acid substitution and altered biological activity of the oncoprotein. ras proteins bind the guanine nucleotides GDP and GTP creating the inactive (GDP bound) and active (GTP bound) states (Fig. 4). Following the binding of GTP to normal ras a further protein, GTPase activating protein (GAP), interacts with the ras/GTP complex promoting GTP hydrolysis and returning ras to the inactive state.27 In contrast, mutant raj forms a complex with GAP but the interaction is incomplete, with no increase in hydrolytic activity so allowing ras to escape downregulation. As a result, mutant ras remains in the GTP-bound state providing a constant simulus to the effector signalling pathway. Other abnormalities may allow activation, particularly an altered GTP: GDP exchange rate with prolonged GTP binding. While the biochemical sequelae of ras activation remain unclear, one can envisage that prolonged stimulation of a growth regulatory pathway contributes to uncontrolled cell division. NON RECEPTOR TYROSINE KINASES Several non-receptor tyrosine kinases are believed to participate in signal transduction although their role is less well understood than that of the receptor tyrosine kinases. The src tyrosine kinase family encompasses a group of closely related proteins that appear to localize at adhesion plaques on the inner aspect of the cell membrane and on internal membranes. pp60c-src, p59fyn, and pp62c-yes kinase activity is increased following PDGF stimulation of NIH3T3 fibroblasts.10 Kinase activation is accompanied by the transient association of the cytoplasmic kinase, the receptor kinase and a PI-3 kinase. Whether the activated status of the complex constituents is mutually interdependent remains unknown. Src kinases and membrane tyrosine kinases phosphorylate a number of common substrates: GAP, c-raf serine-threonine kinase and PI-3 kinase. Given the mutual spectrum of activity it is unclear whedier both forms of kinase act




Termination of signal Fig. 4 Schematic representation of initiation of signal transduction through ras activation. X represents an unknown extracellular growth stimulus. X represents signal transfer between membrane based receptors

to achieve the same response. The target tyrosine residues on the substrates may differ permitting a different regulatory role for each kinase, alternatively sequential phosphorylation at the same site may allow a src kinase to amplify a membrane tyrosine kinase initiated signal.



The oncogene c-abl encodes a cytoplasmic tyrosine kinase implicated in human malignant disease.28 90% of patients with chronic myeloid leukaemia have a characteristic cytogenetic abnormality, the Philadelphia chromosome. This represents an altered chromosome 22 following the balanced reciprocal translocation, t(9,22)(q34,qll). The translocation results in the transfer of the c-abl proto-oncogene from its normal position on chromosome 9 to chromosome 22 adjacent to a gene of unknown function. The exact breakpoint on chromosome 22 is variable and referred to as the breakpoint cluster region (bcr). The bcr-abl juxtaposition results in a chimeric fusion protein with enhanced tyrosine kinase activity. It is tempting to postulate that greater kinase activity augments cytoplasmic signal transduction and that this contributes in some manner to the proposed role of c-abl in tumour initiation and progression. SERENE-THREONINE KINASES The activation of PKC, a serine-threonine protein kinase, following DAG production via the phosphatidylinositol (PI) and phosphocholine pathways (PC) has been discussed. Several members of the PKC gene family are recognized.24'25 Activation of the PI and PC pathways results in the transfer of the inactive cytosolic PKC to membrane sites where the interaction of phospholipid, calcium and DAG result in PKC activation. The local increase of calcium is also believed to activate a calcium dependent protease which cleaves PKC into 60 kD and 50 kD active fragments. The fragments subsequently phosphorylate target proteins thereby continuing the signal transduction pathway.29 Activated PKC phosphorylates several membrane receptors (EGF, T-cell receptor), however the downstream signalling targets preceding AP-1 induction of c-fos, c-jun expression remain unknown. Speculation has arisen that a mutant member of the protein kinase C family may act as an oncogene.30 Other oncogene encoding serine-threonine kinases have been identified, c-raf, c-mos, rel andpim-l (Table 1). The c-ra/product is phosphorylated following PDGF receptor activation, c-raf may act as a key regulatory element interposed between the various signal transduction molecules: membrane receptors, membrane associated tyrosine kinases, guanine nucleotide binding proteins and the nuclear proteins. Moreover activated c-raf may migrate from the cell membrane to the nucleus to alter the action of nuclear



proteins, however the targets of serine-threonine kinase action remain unknown. SUMMARY Details of the signal transduction pathways that relay information between the cell surface and the nucleus are incomplete. A number of en2ymatic cascades form elements of the signalling mechanisms, however in all cases proximal or distal elements of the pathways remain unrecognized. Following the activation of specific receptors the cytoplasmic pathways mediate the transfer of the growth signal eventually resulting in the production of specific factors controlling gene expression. Interestingly most oncogenes encode proteins whose location and action strongly suggest a role in signal transduction. Clearly aberrant signal transduction proteins may contribute to the continuous growth stimulus thought to exist in malignant cells. Most malignant tumours show great morphological and genetic heterogeneity. In normal proliferation individual cell types vary in their requirements for both growth signals and growth regulatory pathways. In malignant disease it is unclear whedier natural selection and clonal expansion result in a diverse malignant cell population capable of utilizing a variety of signal transduction pathways. Inhibitors of cytoplasmic protein kinases may prove to be a viable therapeutic strategy. Already the anti-oestrogen tamoxifen has been demonstrated to be an inhibitor of protein kinase C. 31 This action may be important in the antitumour properties not dependent on oestrogen receptor blockade, and may provide the basis for development of other protein kinase inhibitors. A long-term goal must be the realization of new treatment modalities that combine the interruption of abnormal signal transduction with the clinical aim of good normal tissue tolerance. The determination of normal growth regulatory mechanisms and the recognition of exploitable differences between normal and tumour cells remains a clear prerequisite. Nevertheless the identification of cell-specific signal transduction abnormalities holds promise for new tumour specific therapeutic approaches. REFERENCES 1 Rozengurt E. Early signals in the mitogenic response. Science 1986; 234: 161-166



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25 Nishizuka Y. The molecular heterogeneity of protein kinasc C and its implications for cellular regulation. Nature 1988; 334: 661-668 26 Bos. ras oncogenes in human cancer: a review. Cancer Res 1989; 49: 46824689 27 McCormick F. The world according to GAP. Oncogene 1990; 5: 1281-1283 28 Boehm T, Rabbitts TH. A chromosomal basis of lymphoid malignancy in man. Eur J Biochem 1989; 185: 1-17 29 Edelman AM, Blumenthal DK, Krebs EG. Protein serine/threonine kinases Annu Rev Biochem 1987; 56: 567-613 30 Druker BJ, Mamon HJ, Roberts TM. Oncogenes, growth factors and signal transduction. N Eng J Med 1989; 321: 1383-1391 31 Weinstein BI. The origins of human cancer: molecular mechanisms of carcinogenesis and their implications for cancer prevention and treatment— Twenty-seventh G.H.A. Clowes Memorial Award Lecture. Cancer Res 1988; 48: 4135^1143

Signal transduction.

Ordered cell proliferation relies on a complex interplay between diverse cell types, interstitial stroma and organ vasculature. At a cellular level th...
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