An Endogenous Inhibitor of Focal Adhesion Kinase Blocks Rac1/JNK but Not Ras/ERK-dependent Signaling in Vascular Smooth Muscle Cells

Humoral factors and extracellular matrix are critical co-regulators of smooth muscle cell (SMC) migration and proliferation. We reported previously that focal adhesion kinase (FAK)-related non-kinase (FRNK) is expressed selectively in SMC and can inhibit platelet-derived growth factor BB homodimer (PDGF-BB)-induced proliferation and migration of SMC by attenuating FAK activity. The goal of the current studies was to identify the mechanism by which FAK/FRNK regulates SMC growth and migration in response to diverse mitogenic signals. Transient overexpression of FRNK in SMC attenuated autophosphorylation of FAK at Tyr-397, reduced Src family-dependent tyrosine phosphorylation of FAK at Tyr-576, Tyr-577, and Tyr-881, and reduced phosphorylation of the FAK/Src substrates Cas and paxillin. However, FRNK expression did not alter the magnitude or dynamics of ERK activation induced by PDGF-BB or angiotensin II. Instead, FRNK expression markedly attenuated PDGF-BB-, angiotensin II-, and integrin-stimulated Rac1 activity and attenuates downstream signaling to JNK. Importantly, constitutively active Rac1 rescued the proliferation defects in FRNK expressing cells. Based on these observations, we hypothesize that FAK activation is required to integrate integrin signals with those from receptor tyrosine kinases and G protein-coupled receptors through downstream activation of Rac1 and that in SMC, FRNK may control proliferation and migration by buffering FAK-dependent Rac1 activation. Humoral factors and extracellular matrix are critical co-regulators of smooth muscle cell (SMC) migration and proliferation. We reported previously that focal adhesion kinase (FAK)-related non-kinase (FRNK) is expressed selectively in SMC and can inhibit platelet-derived growth factor BB homodimer (PDGF-BB)-induced proliferation and migration of SMC by attenuating FAK activity. The goal of the current studies was to identify the mechanism by which FAK/FRNK regulates SMC growth and migration in response to diverse mitogenic signals. Transient overexpression of FRNK in SMC attenuated autophosphorylation of FAK at Tyr-397, reduced Src family-dependent tyrosine phosphorylation of FAK at Tyr-576, Tyr-577, and Tyr-881, and reduced phosphorylation of the FAK/Src substrates Cas and paxillin. However, FRNK expression did not alter the magnitude or dynamics of ERK activation induced by PDGF-BB or angiotensin II. Instead, FRNK expression markedly attenuated PDGF-BB-, angiotensin II-, and integrin-stimulated Rac1 activity and attenuates downstream signaling to JNK. Importantly, constitutively active Rac1 rescued the proliferation defects in FRNK expressing cells. Based on these observations, we hypothesize that FAK activation is required to integrate integrin signals with those from receptor tyrosine kinases and G protein-coupled receptors through downstream activation of Rac1 and that in SMC, FRNK may control proliferation and migration by buffering FAK-dependent Rac1 activation. Smooth muscle cell (SMC) 1The abbreviations used are: SMC, smooth muscle cell; PDGF, platelet-derived growth factor; PBS, phosphate-buffered saline; Ab, antibody; ECM, extracellular matrix; Ang II, angiotensin II; FAK, focal adhesion kinase; FRNK, FAK-related non-kinase; GFP, green fluorescent protein; CAS, p130 Crk-associated substrate; MEK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase; ERK, extracellular signal-regulated kinase; PI3K, phosphatidylinositol 3-kinase; PAK, p21-activated kinase 1; JNK, c-Jun N-terminal kinase; BrdUrd, bromodeoxyuridine; GFRNK, cells expressing GFP-FRNK; IGF-1, insulin-like growth factor-1; ET-1, endothelin-1; DsV, pDsRedC1 vector; DsRacL61, pDsRedC1-tagged RacL61; GST, glutathione S-transferase; pY, phosphotyrosine. proliferation is certainly important during vascular development, but it is clear that increased SMC proliferation and migration are important contributors to the pathogenesis of several important cardiovascular disease states including atherosclerosis, restenosis, and hypertension. A large number of extrinsic cues (growth factors, extracellular matrix, cell-cell interactions, etc.) have been identified that regulate SMC growth and migration (1Berk B.C. Physiol. Rev. 2001; 81: 999-1030Crossref PubMed Scopus (341) Google Scholar, 2Owens G.K. Circ. Res. 1996; 79: 1054-1055Crossref PubMed Scopus (56) Google Scholar). However, the precise cellular signaling mechanisms involved are not completely understood, and very little is known about how (or if) these signaling pathways are integrated. The majority of soluble SMC mitogens can be broadly divided into two groups, activators of receptor tyrosine kinases (i.e. platelet-derived growth factor BB homodimer (PDGF-BB), basic fibroblast growth factor, insulin-like growth factor-1 (IGF-1), and activators of G protein-coupled receptors (i.e. angiotensin II (Ang II), thrombin, endothelin-1 (ET-1); see Ref. 2Owens G.K. Circ. Res. 1996; 79: 1054-1055Crossref PubMed Scopus (56) Google Scholar). A large body of evidence indicates that members of both groups activate (to varying degrees) the Ras/Raf/MEK/ERK and PI3K/Rac/PAK/JNK kinase cascades, phospholipase C, and protein kinase C signaling pathways, among others (1Berk B.C. Physiol. Rev. 2001; 81: 999-1030Crossref PubMed Scopus (341) Google Scholar). Interestingly, it is becoming clear that the mitogenic responses elicited by many of these factors are dependent upon extracellular matrix (ECM)/integrin interactions. For example, when cultured fibroblasts are held in suspension, PDGF-, epidermal growth factor-, and lysophosphatidic acid-stimulated ERK activity is markedly reduced compared with cells plated on fibronectin (3Lin T.H. Chen Q. Howe A. Juliano R.L. J. Biol. Chem. 1997; 272: 8849-8852Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar, 4Renshaw M.W. Ren X.D. Schwartz M.A. EMBO J. 1997; 16: 5592-5599Crossref PubMed Scopus (270) Google Scholar). Integrin-mediated activation of the non-receptor tyrosine kinase, focal adhesion kinase (FAK), is a critical step in integrin signaling and may be important for growth factor signaling, as well. In support of this idea, several mitogens (including PDGF-BB, Ang II, IGF-1, and ET-1) stimulate FAK tyrosine phosphorylation in an adhesion-dependent manner (5Polte T.R. Naftilan A.J. Hanks S.K. J. Cell. Biochem. 1994; 55: 106-119Crossref PubMed Scopus (115) Google Scholar, 6Sieg D.J. Hauck C.R. Ilic D. Klingbeil C.K. Schaefer E. Damsky C.H. Schlaepfer D.D. Nat. Cell Biol. 2000; 2: 249-256Crossref PubMed Scopus (1080) Google Scholar, 7Nakamura M. Nagano T. Chikama T. Nishida T. Biochem. Biophys. Res. Commun. 1998; 242: 16-20Crossref PubMed Scopus (40) Google Scholar, 8Kovacic-Milivojevic B. Roediger F. Almeida E.A. Damsky C.H. Gardner D.G. Ilic D. Mol. Biol. Cell. 2001; 12: 2290-2307Crossref PubMed Scopus (81) Google Scholar). In addition, Renshaw et al. (9Renshaw M.W. Price L.S. Schwartz M.A. J. Cell Biol. 1999; 147: 611-618Crossref PubMed Scopus (190) Google Scholar) have shown that integrin augmentation of growth factor-mediated signaling to ERK2 appears to be dependent upon FAK activation, because the inhibition of mitogen-activated protein kinase activation observed in suspended cells can be rescued by overexpression of activated FAK. Furthermore, integrin-mediated autophosphorylation of FAK on Tyr-397 leads to recruitment and activation of Src and PI3K and subsequent downstream activation of Ras/ERK or Rac/JNK cascades (10Schaller M.D. J. Endocrinol. 1996; 150: 1-7Crossref PubMed Scopus (75) Google Scholar, 11Parsons J.T. J. Cell Sci. 2003; 116: 1409-1416Crossref PubMed Scopus (1163) Google Scholar). Interestingly, our laboratory showed recently that FAK appears to be regulated in a unique fashion in SMC. We reported that the noncatalytic C-terminal domain of FAK, termed FAK related non-kinase (FRNK), is selectively expressed in SMC with very high levels found in the large arterioles. FRNK transcription results from the utilization of an alternative start site within the FAK gene, and FRNK expression is independently regulated by a distinct promoter embedded within FAK intronic sequences (12Taylor J.M. Mack C.P. Nolan K. Regan C.P. Owens G.K. Parsons J.T. Mol. Cell. Biol. 2001; 21: 1565-1572Crossref PubMed Scopus (144) Google Scholar, 13Nolan K. Lacoste J. Parsons J.T. Mol. Cell. Biol. 1999; 19: 6120-6129Crossref PubMed Scopus (97) Google Scholar). Interestingly, whereas FAK protein levels remain relatively constant, FRNK protein levels in vivo are dynamically regulated with increased FRNK expression in the neonatal period and from 2 to 3 weeks following balloon injury. of expression with the of SMC proliferation that is known to these that FRNK may be an important of SMC growth G.K. Circ. Res. 1996; 79: 1054-1055Crossref PubMed Scopus (56) Google Scholar). In support of this idea, we have shown that overexpression of in SMC completely the in and the mitogenic of In addition, SMC migration PDGF-BB (12Taylor J.M. Mack C.P. Nolan K. Regan C.P. Owens G.K. Parsons J.T. Mol. Cell. Biol. 2001; 21: 1565-1572Crossref PubMed Scopus (144) Google Scholar). these that FRNK as an of FAK activity and that expression in vivo may to FAK-dependent and signals. In this we to identify the mechanism by which FRNK attenuates growth factor and adhesion signaling in SMC. that in to cell FAK/FRNK signaling not ERK activity in SMC. Instead, our that in SMC, Rac1 activation may be a in growth and FAK-dependent cell proliferation. and an FAK and the Rac1 from The Tyr-576, Tyr-577, and from was from The and mitogen-activated protein kinase was from Cell with the protein and was a of two the C-terminal domain of and by of 1997; 16: PubMed Scopus Google Scholar). The was by of The Ang II, and fibronectin from and was from and and FRNK by as previously (12Taylor J.M. Mack C.P. Nolan K. Regan C.P. Owens G.K. Parsons J.T. Mol. Cell. Biol. 2001; 21: 1565-1572Crossref PubMed Scopus (144) Google Scholar). The an N-terminal was by into the and in the Cell and SMC from by as previously M.A. Google Scholar). used from and in and For cells in with or for to In cells for by with PDGF-BB or Ang II for the For the adhesion cells in in by and in held in or plated on for the In SMC following the plated on II and with as for and with PDGF-BB for with and and in in for an in PBS, for 3 with in was by with and with in for for with in to at and SMC plated on II as with of pDsRedC1 or pDsRedC1-tagged following cells with or for as and with or PDGF-BB with of for at for with and with in the at for was used following the by a at with a and with and by For the SMC plated in and as with the that the was to the for 2 to cell proliferation as the this period the of was a and in 2 and and by of of cell with of the for 2 at by a with protein For the The by and with and two with in and on a and to the at a which was used at in by with protein or at a with activity was by a following the In of from PDGF-BB or SMC was with of and at by and with and in kinase and 2 of The was at for and by the of on an to a with and as of was from as previously J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). or SMC and with PDGF-BB or Ang II as in A and and by for at at K. Mol. Biol. Cell. 2001; 12: PubMed Scopus Google Scholar). of was with of and at for The by and two in and in and to was an as We reported previously that overexpression of in cultured by in a in FRNK protein an FRNK to FAK of with observed in neonatal and is to inhibit both FAK activity and proliferation and to the signaling pathways by FRNK expression in SMC, we the of FRNK overexpression on cellular In of SMC, tyrosine attenuated in in with or control cells The protein is FAK because FAK with this and FRNK overexpression in SMC autophosphorylation of Tyr-397 as reported previously (12Taylor J.M. Mack C.P. Nolan K. Regan C.P. Owens G.K. Parsons J.T. Mol. Cell. Biol. 2001; 21: 1565-1572Crossref PubMed Scopus (144) Google Scholar). 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Cell. 1999; PubMed Scopus Google Scholar) we FRNK alter the of ERK activity. shown in and C, FRNK expression did not alter the of ERK activation at from to 3 In addition, we observed in the of ERK to as by an kinase that phosphorylation of a protein that in SMC, FRNK migration and proliferation in an signaling pathways known to regulate both proliferation and migration activation of the of the Interestingly, Rac1 been shown previously L.S. J. Schwartz M.A. Mol. Biol. Cell. 1998; PubMed Scopus Google Scholar, A. D. T. M. et Biol. Full Text Full Text PDF PubMed Scopus Google Scholar) to be activated both by receptors and following of We used a to Rac1 activation in SMC a protein to active but not shown in this protein activated but not when these in cells. this we have shown that PDGF-BB induced a activation of Rac1 in SMC. an in Rac1 which and 3 following shown in overexpression of activity and markedly attenuated Rac1 activity in SMC. In addition, activation of kinase known to be downstream of Rac1 was attenuated in the expressing cells Rac1 activation the of distinct an important during cell L.S. J. Schwartz M.A. Mol. Biol. Cell. 1998; PubMed Scopus Google Scholar, A. Cell. 81: Full Text PDF PubMed Scopus Google Scholar, B. B. 1997; PubMed Scopus Google we FRNK expression in SMC alter this in SMC. in PDGF-BB a of and a the of and of the of the see In of cells did not in in these that FRNK expression attenuates the activation of Rac1 and signals in SMC. inhibition of Rac1 was the for the defects induced by FRNK, we the of activated Rac1 to proliferation in FRNK cells. this SMC with or to with and cells with and for to with our FRNK overexpression attenuated by to a with cells in compared with see Importantly, Rac1 little on in expressing overexpression of constitutively active rescued the of FRNK on cell proliferation compared with FRNK that of FRNK expressed both that Rac1 downstream of FAK/FRNK to control SMC proliferation. inhibition of Rac1 activity be a mechanism by which FRNK attenuates SMC we the of FRNK to inhibit Ang We found that overexpression of FRNK Ang cell growth the by a as by of the studies reported Circ. Res. 2000; PubMed Scopus Google Scholar) and that FRNK can inhibit signals induced by G protein-coupled as as receptor tyrosine Ang II been shown to stimulate Rac1 activity in SMC K. A. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar) and cell we this be by as shown in Ang II a in Rac1 activity in SMC, and this was attenuated by expression of shown in and C, the of Ang ERK activation the of Ang II required for ERK activation by overexpression of in SMC. that Ang II stimulate FAK activity and that this activity is by overexpression of FRNK appears to both Ang and mitogenic signaling on ERK activity. signaling through many SMC mitogens is dependent on ECM, but the precise mechanisms involved in this have not been In cell have been shown to to the activation of Rac1 A. M. E. Mol. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). we SMC on fibronectin stimulate the activation of Rac1 in SMC and expression of FRNK alter Rac1 activation. shown in SMC on fibronectin a activation of Rac1 that at and overexpression of FRNK attenuated this response at In overexpression of FRNK little on ERK activity. that FRNK attenuates FAK-dependent activation of Rac1 in response to PDGF-BB, Ang II, and Based on these observations, we hypothesize that Rac1 activation may be a in growth factor and cell proliferation and migration in SMC and that FRNK may to regulate signaling through diverse pathways at this mitogenic signaling pathways that regulate SMC growth and A of that regulate SMC growth and migration are known to regulate Rac/JNK and Ras/ERK We hypothesize that FAK activation is required to integrate signals from receptor tyrosine and G protein-coupled receptors to the downstream activation of In SMC, FRNK may control proliferation and migration by buffering this FAK-dependent studies have a for the non-receptor tyrosine kinase, FAK, in the of migration and proliferation. FAK is activated by growth factor and G protein-coupled receptor and may to integrate downstream signals from a of the precise mechanisms by which FAK regulates signaling from these diverse pathways have not been J.T. J. Cell Sci. 2003; 116: 1409-1416Crossref PubMed Scopus (1163) Google Scholar). In this we the of growth factor and integrin signaling through FAK in the of vascular SMC proliferation. we reported previously (12Taylor J.M. Mack C.P. Nolan K. Regan C.P. Owens G.K. Parsons J.T. Mol. Cell. Biol. 2001; 21: 1565-1572Crossref PubMed Scopus (144) Google Scholar, A. Parsons T. 1996; PubMed Scopus Google Scholar, M.D. Parsons J.T. Cell Biol. 1994; PubMed Scopus Google FAK activity appears to be regulated in a unique fashion in SMC expression of the C-terminal domain of FAK can as an of FAK In we have shown the that FRNK is expressed selectively in SMC with high levels observed in the that FRNK expression is regulated during and following vascular and that expression of FRNK in cultured SMC migration and proliferation (12Taylor J.M. Mack C.P. Nolan K. Regan C.P. Owens G.K. Parsons J.T. Mol. Cell. Biol. 2001; 21: 1565-1572Crossref PubMed Scopus (144) Google Scholar). that FRNK expression may on FAK-dependent signaling in SMC. we that expression of FRNK in SMC mitogenic signaling from diverse factors by attenuating FAK-dependent of the Rac/JNK but not the Ras/ERK Ras/ERK and Rac/JNK are two of the pathways known to be of cell proliferation and Cell adhesion to extracellular matrix regulates Ras/ERK signaling in many cell and studies have shown that growth factor signaling to ERK is Juliano R.L. 12: PubMed Scopus Google Scholar). of evidence a for FAK activation in growth several mitogens (including PDGF-BB, Ang II, IGF-1, and ET-1) stimulate FAK tyrosine phosphorylation in an adhesion-dependent manner (5Polte T.R. Naftilan A.J. Hanks S.K. J. Cell. Biochem. 1994; 55: 106-119Crossref PubMed Scopus (115) Google Scholar, 6Sieg D.J. Hauck C.R. Ilic D. Klingbeil C.K. Schaefer E. Damsky C.H. Schlaepfer D.D. Nat. 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