Cadherins and Pak1 control contact inhibition of proliferation by Pak1-betaPIX-GIT complex-dependent regulation of cell-matrix signaling.
It is crucial for organ homeostasis that epithelia have effective mechanisms to restrict motility and cell proliferation in order to maintain tissue architecture. On the other hand, epithelial cells need to rapidly and transiently acquire a more mesenchymal phenotype, with high levels of cell motility and proliferation, in order to repair epithelia upon injury. Cross talk between cell-cell and cell-matrix signaling is crucial for regulating these transitions. The Pak1-betaPIX-GIT complex is an effector complex downstream of the small GTPase Rac1. We previously showed that translocation of this complex from cell-matrix to cell-cell adhesion sites was required for the establishment of contact inhibition of proliferation. In this study, we provide evidence that this translocation depends on cadherin function. Cadherins do not recruit the complex by direct interaction. Rather, we found that inhibition of the normal function of cadherin or Pak1 leads to defects in focal adhesion turnover and to increased signaling by phosphatidylinositol 3-kinase. We propose that cadherins are involved in regulation of contact inhibition by controlling the function of the Pak1-betaPIX-GIT complex at focal contacts.
Liu
Fengming
F
Department of Surgery, University of Chicago, Chicago, IL 60637, USA.
Jia
Liwei
L
Thompson-Baine
Ann-Marie
AM
Puglise
Jason M
JM
Ter Beest
Martin B A
MB
Zegers
Mirjam M P
MM
D022005:Adherens Junctions / Q000378:metabolism; D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D002867:Chromones / Q000378:metabolism; D003260:Contact Inhibition / Q000502:physiology*; D004285:Dogs; D005109:Extracellular Matrix / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009025:Morpholines / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D064067:Rho Guanine Nucleotide Exchange Factors; D015398:Signal Transduction / Q000502:physiology*; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
D015820:Cadherins; D002867:Chromones; D020662:Guanine Nucleotide Exchange Factors; D020928:Mitogen-Activated Protein Kinases; D009025:Morpholines; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering; D064067:Rho Guanine Nucleotide Exchange Factors; D054462:p21-Activated Kinases; D020830:rac1 GTP-Binding Protein; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one