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The mechanisms through which heregulin (HRG) regulates the activities of breast cancer cells are currently unknown. We demonstrate that HRG stimulation of noninvasive breast cancer cells enhanced the conversion of globular to filamentous actin and the formation of membrane ruffles, stress fibers, filopodia, and lamellipodia and accompanied by increased cell migration. In addition, HRG triggered a rapid stimulation of p21-activated kinase1 (PAK1) activity and its redistribution into the leading edges of motile cells. The HRG-induced stimulation of PAK1 kinase activity followed phosphatidylinositol-3 kinase (PI-3 kinase) activation. Inhibition of PI-3 kinase activity blocked the activation of PAK1 kinase and also blocked cell migration in response to HRG. Furthermore, direct inhibition of PAK1 functions by the dominant-negative mutant suppressed the capacity of HRG to reorganize actin cytoskeleon structures. We also demonstrated that HRG stimulation promoted physical interactions between PAK1, actin, and human epidermal growth factor receptor 2 (HER2) receptors, and these interactions were dependent on the activation of PI-3 kinase. The blockade of HER2 receptor by an anti-HER2 monoclonal antibody resulted in the inhibition of HRG-mediated stimulation of PI-3 kinase/PAK pathway and also the formation of motile actin cytoskeleton structures but not extracellular signal-regulated kinases. These findings suggest a role of PI-3 kinase/PAK1-dependent reorganization of the cortical actin cytoskeleton in HRG-mediated increased cell migration, and these changes may have significant consequences leading to enhanced invasion by breast cancer cells. The mechanisms through which heregulin (HRG) regulates the activities of breast cancer cells are currently unknown. We demonstrate that HRG stimulation of noninvasive breast cancer cells enhanced the conversion of globular to filamentous actin and the formation of membrane ruffles, stress fibers, filopodia, and lamellipodia and accompanied by increased cell migration. In addition, HRG triggered a rapid stimulation of p21-activated kinase1 (PAK1) activity and its redistribution into the leading edges of motile cells. The HRG-induced stimulation of PAK1 kinase activity followed phosphatidylinositol-3 kinase (PI-3 kinase) activation. Inhibition of PI-3 kinase activity blocked the activation of PAK1 kinase and also blocked cell migration in response to HRG. Furthermore, direct inhibition of PAK1 functions by the dominant-negative mutant suppressed the capacity of HRG to reorganize actin cytoskeleon structures. We also demonstrated that HRG stimulation promoted physical interactions between PAK1, actin, and human epidermal growth factor receptor 2 (HER2) receptors, and these interactions were dependent on the activation of PI-3 kinase. The blockade of HER2 receptor by an anti-HER2 monoclonal antibody resulted in the inhibition of HRG-mediated stimulation of PI-3 kinase/PAK pathway and also the formation of motile actin cytoskeleton structures but not extracellular signal-regulated kinases. These findings suggest a role of PI-3 kinase/PAK1-dependent reorganization of the cortical actin cytoskeleton in HRG-mediated increased cell migration, and these changes may have significant consequences leading to enhanced invasion by breast cancer cells. heregulin-β1 p21-activated kinase myelin basic protein phosphatidylinositol-3 kinase, HA, hemagglutinin epitope antibody monoclonal Ab epidermal growth factor human EGF receptor matrix metalloproteinase. Proto-oncogenes are a group of normal genes that play important roles in the regulation of cell proliferation, differentiation, and viability. Abnormalities in the expression, structure, or activity of proto-oncogene products contribute to the development and maintenance of the malignant phenotype. For example, HER21 (also known as c-erbB2 or c-neu) encodes a 185-kDa transmembrane glycoprotein with intrinsic tyrosine kinase activity (1Stern D.F. Heffernan P.A. Weinberg R.A. Mol. Cell. Biol. 1986; 6: 1729-1740Crossref PubMed Scopus (286) Google Scholar) that has been shown to be overexpressed, amplified, or both, in a number of human malignancies, including breast cancer (2Slamon D.J. Clark G.M. Wong S.G. Levin W.J. Ullrich A. McGuire W.L. Science. 1987; 235: 177-181Crossref PubMed Scopus (9910) Google Scholar). Overexpression of the HER2 receptor is associated with increased progression and metastasis, an aggressive clinical course, and decreased disease-free survival in human breast cancer (3Slamon D.J. Godolphin W. Jones L.A. Holt J.A. Wong S.G. Keith D.E. Levin W.J. Stuart S.G. Udove J. Ullrich A. Science. 1989; 244: 707-712Crossref PubMed Scopus (6247) Google Scholar, 4Muss H.B. Thor A.D. Berry D.A. Kute T. Liu E.T. Koerner F. Cirrincione C.T. Budman D.R. Wood W.C. Barcos M. New Eng. J. Med. 1994; 330: 1260-1266Crossref PubMed Scopus (968) Google Scholar). Recently, two additional members, HER3 and HER4, have been added to the human EGF receptor (HER) family. All of these receptors share sequence homology with the tyrosine kinase domain of HER1 (5Plowman G.D. Culouscou J.M. Whitney G.S. Green J.M. Carlton G.W. Foy L. Neubauer M.G. Shoyab M. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 1746-1750Crossref PubMed Scopus (688) Google Scholar). Overexpression of some growth factor receptors has been shown to induce transformed properties in recipient cells (6Heidaran M.A. Fleming T.P. Bottaro D.P. Bell G.I. DiFiore P.P. Aaronson S.A. Oncogene. 1990; 5: 1265-1270PubMed Google Scholar), possibly because of excessive activation of signal transduction pathways. The regulation of HER family members is complex, as they can be transactivated by heterodimeric interaction between two HER members and thus can utilize multiple pathways to execute their biological functions (7Alroy L. Yarden Y. FEBS Lett. 1997; 410: 83-86Crossref PubMed Scopus (654) Google Scholar, 8Hynes N.C. Stern D.F. Biochim. Biophys. Acta. 1994; 1198: 165-184Crossref PubMed Scopus (1001) Google Scholar). For example, HER3 and HER4 receptors bind to more than a dozen isoforms of the heregulins (HRGs) or neu differentiation factors (9Peles E. Bacus S.S. Koski R.A. Lu H.S. Wen D. Ogden S.G. Levy R.B. Yarden Y. Cell. 1992; 69: 205-216Abstract Full Text PDF PubMed Scopus (478) Google Scholar, 10Wen D. Peles E. Cupples R. Suggs S.V. Bacus S.S. Luo Y. Trail G. Hu S. Silbiger S.M. Levy R.B. Cell. 1992; 69: 559-572Abstract Full Text PDF PubMed Scopus (526) Google Scholar), and they can activate the HER2 receptor as a result of HER2/HER3 or HER2/HER4 heterodimeric interactions (7Alroy L. Yarden Y. FEBS Lett. 1997; 410: 83-86Crossref PubMed Scopus (654) Google Scholar, 8Hynes N.C. Stern D.F. Biochim. Biophys. Acta. 1994; 1198: 165-184Crossref PubMed Scopus (1001) Google Scholar). A ligand that interacts with HER2 in the absence of other HER family members has yet to be identified. Although the significance of HER2 in breast cancer is well established, the mechanism involved remains poorly understood. It has been proposed that this may involve constitutive activation of the intrinsic tyrosine kinase activity due to either mutations in the HER2 gene, overexpression, and/or transactivation via receptor-dimerization with other HER members. HER3 is unique among HER family members, as it has an impaired tyrosine kinase domain due to substitution of three amino acids in the kinase domain (11Guy P.M. Platko J.V. Cantley L.C. Cerione R.A. Carraway III, K.L. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 8132-8136Crossref PubMed Scopus (595) Google Scholar). Despite the kinase dead nature of HER3, HRG binding to HER3 leads to increased HER3 tyrosine phosphorylation, probably due to formation of a high-affinity co-receptor complex through heterodimeric interaction with HER2 (12Horan T. Wen J. Arakawa T. Liu N. Brankow D. Hu S. Ratzkin B. Philo J.S. J. Biol. Chem. 1995; 270: 24604-24608Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar). 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In to HER2 overexpression, that the HRG pathway may be involved in the progression of breast cancer cells to a more phenotype. In the the by which may in the of in breast demonstrate that HRG stimulation of a noninvasive human breast cancer cell leads to the activation of PAK1 kinase via PI-3 an increased physical between the PAK1, actin, and HER2 and a redistribution of PAK1 the leading These interactions were dependent on the activation of PI-3 kinase by HRG. In addition, these changes were accompanied by the development of and stress fibers, and they also increased the migration of breast cancer cells through a human breast cancer and cells D. E. 1993; Scopus Google Scholar, R. M. Ratzkin Liu N. A. J. Cell. 1995; Google Scholar) were in with EGF receptor HER2 and HER3 and were HER2 and EGF receptors have been R. J. Mol. Cell. Biol. PubMed Scopus Google Scholar, J. R. J. Biol. Chem. 1993; Full Text PDF PubMed Google Scholar). by a actin human actin as R. Proc. Natl. Acad. Sci. U. S. 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The shown in demonstrate that HRG is a potent cell growth of HER2 has been shown to be associated with an aggressive clinical in human breast cancer H.B. Thor A.D. Berry D.A. Kute T. Liu E.T. Koerner F. Cirrincione C.T. Budman D.R. Wood W.C. Barcos M. New Eng. J. Med. 1994; 330: 1260-1266Crossref PubMed Scopus (968) Google Scholar), also the of HER2 on the cell migration and reorganization of well cells D. E. 1993; Scopus Google Scholar, R. M. Ratzkin Liu N. A. J. Cell. 1995; Google Scholar). demonstrated that cells were more motile and have more actin the edges as with cells but to HRG by enhanced actin and cell migration not activation of PAK1, the of has been shown to result in the including a formation of lamellipodia and M.A. S. G.M. J. Biol. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, S. L.C. S.S. G.M. J. Biol. 1997; PubMed Scopus Google Scholar), the of PAK1 in the of HRG. this PAK1 is by HRG in cells. and cells were with and PAK1 its kinase activity as The shown in 2 a demonstrated that HRG PAK1 kinase and of In to PAK1 kinase, the activation of PI-3 kinase has been also shown to induce actin reorganization and membrane Y. A. A. B. F. J. 1994; PubMed Scopus Google Scholar), possibly through HRG is known to activate PI-3 kinase in breast cancer the role of PI-3 kinase in HRG-mediated in structures. this the between the stimulation of HER2 and PI-3 kinase and PAK1 shown in activation of HER2 receptors by binding of HRG to its receptors resulted in rapid in the activities of three kinases. The PI-3 kinase activity to a with cells of HRG and to It that HRG-induced activation of PAK1 followed the of PI-3 kinase activation with a activation by of and kinase the of to the in cells. HRG-induced activation of PAK1 followed the of PI-3 kinase, PAK1 activation is a of HRG-induced activation of PI-3 kinase. The shown in demonstrate that inhibition of PI-3 kinase by a accompanied by inhibition of HRG-induced activation of PAK1 in cells and of cells with also accompanied by of HRG-mediated stimulation of cell migration through a membrane 2 The shown in 2 also demonstrate that the of it blocked PAK1 activity and cell migration in cells. It is that a that to PI-3 kinase activity also other that are not to The in the redistribution of PAK1 the motile edges in the cells. In to the cell but in the of the that the leading of a cell that due to cell A also be the cell cells of it with as or of and not its activation as have been S. L.C. S.S. G.M. J. Biol. 1997; PubMed Scopus Google Scholar). have been shown to on its and on its with M.A. S. G.M. J. Biol. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, S. L.C. S.S. G.M. J. 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Although as a protein kinase, this of may thus with and/or The shown in demonstrate that inhibition of PAK1 in cells with the PAK1 mutant resulted in blockade of HRG-mediated actin In but it not In actin in the cells The of dominant-negative PAK1 on actin structures in more than of the cells. of the of on HRG-induced reorganization of actin or cell In these that the leading to actin reorganization be blocked by PI-3 kinase and/or PAK1 kinase. HRG triggered of PAK1 into the leading of the interactions between the HER2 receptor and the PAK1 and actin by PAK1 with an anti-HER2 A but significant of HER2 receptor associated with in cells and a cell or cells were with normal and of actin or HER2 or PAK1 and The interactions among PAK1, and actin were dependent on the activation of PI-3 kinase by as of cells with the PI-3 kinase the interaction between PAK1 and HER2 receptor and actin The shown in also demonstrate that interaction between the HER2 receptor and PAK1 in and HRG stimulation the interactions among HER2 PAK1, and These are with the of motile cytoskeleton structures in cells. of other that cells have more PAK1 activity than cells not These suggest that HRG physical interactions among PAK1, and It remains to be these interactions are direct or through other the of HER2 receptors in HRG-induced motile in breast cancer the of an anti-HER2 R. J. Mol. Cell. Biol. PubMed Scopus Google Scholar), on the development of motile structures by HRG in an extracellular The shown in a demonstrate that of cells with accompanied by of HRG-mediated development of structures. of anti-HER2 as significant of receptor on the development of structures by HRG. The of anti-HER2 to the cell of breast cancer cells also by the The shown in demonstrate that of cells with and HRG resulted in the of HRG-induced cell migration. of the most important the of migration and/or invasion is the of extracellular matrix by matrix L.A. Cell. Full Text PDF PubMed Scopus Google Scholar), the regulation of by HRG and its by The in that stimulation of cells with HRG leads to a significant in the of as well as its activity in the and these changes be by with the mechanism of of on HRG-mediated functions in the of HER2 receptor by on pathways. cells were with or or an receptor followed by stimulation with HRG and cell were the activation of PAK1, and kinases. shown in of cells with to the activation of HER2 receptor by HRG in resulted in the activation of HER2 receptor accompanied by in the of HRG-induced PI-3 kinase with blocked the HRG-mediated activation of PI-3 kinase by with also resulted in the inhibition of HRG-induced activation of PAK1 kinase and kinase activities to a significant In it to that to the activation of kinase by HRG The shown in a also demonstrate that the activation of HER2 receptor not accompanied by activation of in this thus the of a nature of HER2 activation by in cells. In the has been shown to induce the activation of HER2 pathway in breast cancer cells HER2 receptors J.M. P.A. Wong W.L. Ullrich A. J. Biol. Chem. Full Text PDF PubMed Google Scholar), but not in cells with a normal of HER2 receptors, as as shown in the the findings that may the activation of PI-3 pathway leading to actin but not the leading to activation. the of of in the of an of of on HRG-induced interactions between HER2 and HER3 The shown in that of cells blocked interactions between HER2 and HER3 receptors in because of HER3 receptor with HER2 in cells with and HRG with the cells with HRG or and HRG shown in of HER2 receptor by of with in the of the HER2 receptor and which HER2 receptor via its binding to HER3 or HER4 receptors, has been shown to be associated with the progression of breast cancer cells to a more and aggressive phenotype. the of progression to a more malignant involve physical of cancer and because HRG has been shown to migration in Y. E. D. M. G. W. J. Biol. 1995; PubMed Scopus Google Scholar, D.J. Stern D.F. Google Scholar), the nature of that may be involved in the regulation of cell migration. The that HRG of noninvasive breast cancer cells leads to a significant of cell migration. that HRG is a cell factor is by the of HRG-mediated increased of accompanied by the development of motile as and HRG the formation of stress fibers, the of a leading and membrane the leading HRG the of cells an and HRG also cell and structures cells were on a these that HRG the formation of motile actin cytoskeleton structures and is a potent factor breast cancer cells. the pathways leading to actin the family of the including and has been in the regulation of and of cells. have the p21-activated as a direct of because activation of PAK1 has been shown to result in the changes of by and/or M.A. S. G.M. J. Biol. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, S. L.C. S.S. G.M. J. Biol. 1997; PubMed Scopus Google Scholar). Furthermore, a direct role of in cell migration has been by the physical interaction between PAK1 and in response to M.A. S. G.M. J. Biol. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, S. L.C. S.S. G.M. J. Biol. 1997; PubMed Scopus Google Scholar). In this that HRG PAK1 kinase activity and also its to the leading edges and membrane of the cells a of the HER2 activation to cytoskeleton in breast cancer cells. The of PAK1 activation in HRG the PAK1 activation followed the tyrosine of HER2 PAK1 activity has been shown to be associated with receptor tyrosine J. J. J. Biol. Chem. Full Text PDF PubMed Scopus Google and PAK1 associated with the HER2 receptors in cells and not in cells The significance of PAK1 activation in the of HRG cell the that HRG triggered a of PAK1 to the leading edges of the PAK1 associated with actin in and the of a PAK1 mutant HRG-mediated actin the reorganization of structures. These findings suggest a role of PAK1 activation in HRG-mediated reorganization of motile structures in breast cancer cells. the Y. A. A. B. F. J. 1994; PubMed Scopus Google Scholar) and these suggest that the activation of PI-3 kinase is a growth factor response that may be involved in actin reorganization and membrane The that the stimulation of PAK1 kinase activity PI-3 kinase activation is as it that PI-3 kinase may an signal actin reorganization and cell migration. is by the that inhibition of PI-3 kinase by the accompanied by inhibition of HRG-mediated stimulation of PAK1 activity and cell migration of dominant-negative PI-3 kinase or mutant blocked HRG-mediated reorganization of structures inhibition of PI-3 kinase activity by physical interactions between PAK1 and HER2 receptor and actin in cells and anti-HER2 activation of PI-3 kinase/PAK pathway and HRG-induced cell migration These suggest that PAK1 may be of PI-3 kinase in the HRG leading to reorganization and increased migration of breast cancer cells. in this the role of HER2 receptor in the cell of HRG. The that a growth has the capacity to the biological of including reorganization of actin cytoskeleton and migration of breast cancer is of as it that HRG the HER2 receptor to its in breast cancer cells. is by findings that of cells with anti-HER2 and not an receptor blocked the development of motile structures. the not the mechanism by which anti-HER2 its on the functions of HRG. It is that binding of anti-HER2 to HER2 receptors may to a in the HER2 receptor in a that with its interaction with HER3 or HER4 receptors in response to HRG. it is also that binding to HER2 receptor may that HER2 with HER3 and/or with may the of HER2 interaction with HER3 in response to HRG. In either may result in the blockade of by the formation of HER2/HER3 in cells. the not blocked the activation of the pathway but not that of is a PI-3 kinase binding in the domain of HER3 receptors J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar), may direct of PI-3 kinase by HER3 receptor and kinase may be by In this it is that the activation of HER2 receptor by be due to the formation of are in to these and other of the findings have that anti-HER2 the development of motile structures as well as cell migration. In the have not the that the PI-3 kinase with PAK1 kinase in cells. have shown that the and are of PAK1 kinase and of PI-3 kinase in the pathways. are the roles of and the in HRG In this it to that the of a dominant-negative PAK1 not blocked the reorganization of actin the leading edges but also blocked formation of stress In the stress formation has been shown to activation and tyrosine A. J. 1994; PubMed Scopus Google Scholar). it is that may be in the leading to PAK1 activation in cells. may be or by PAK1 in HRG In either inhibition of PAK1 activity may to of formation of stress fibers, a role in HRG is by that the of by its HRG-mediated formation of stress R. and R. in findings of regulation of actin reorganization and cell migration functions by HRG and its by an anti-HER2 a of HER2 cytoskeleton and breast cancer cell In addition, the of of in the invasion and of breast We with the actin and the PI-3 kinase and
Adam et al. (Thu,) studied this question.