The p21-activated kinase PAK is negatively regulated by POPX1 and POPX2, a pair of serine/threonine phosphatases of the PP2C family.
The Rho GTPases are involved in many signaling pathways and cellular functions, including the organization of the actin cytoskeleton, regulation of transcription, cell motility, and cell division. The p21 (Cdc42/Rac)-activated kinase PAK mediates a number of biological effects downstream of these Rho GTPases (reviewed by [1]). The phosphorylation state of mammalian PAK is highly regulated: upon binding of GTPases, PAK is potently activated by autophosphorylation at multiple sites, although the mechanisms of PAK downregulation are not known. We now report two PP2C-like serine/threonine phosphatases (POPX1 and POPX2) that efficiently inactivate PAK. POPX1 was isolated as a binding partner for the PAK interacting guanine nucleotide exchange factor PIX. The dephosphorylating activity of POPX correlates with an ability to block the in vivo effects of active PAK. Consonant with these effects on PAK, POPX can also inhibit actin stress fiber breakdown and morphological changes driven by active Cdc42(V12). The association of the POPX phosphatases with PAK complexes may allow PAK to cycle rapidly between active and inactive states; it represents a unique regulatory component of the signaling pathways of the PAK kinase family.
Koh
Cheng-Gee
CG
Institute of Molecular and Cell Biology, 30 Medical Drive, 117609, Singapore, Singapore. mcbkohcg@imcb.nus.edu.sg
Tan
E-Jean
EJ
Manser
Edward
E
Lim
Louis
L
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D018797:Cell Cycle Proteins / Q000378:metabolism; D015536:Down-Regulation; D004789:Enzyme Activation; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D005810:Multigene Family; D010641:Phenotype; D010749:Phosphoprotein Phosphatases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D054648:Protein Phosphatase 2; D000071636:Protein Phosphatase 2C; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins; D064067:Rho Guanine Nucleotide Exchange Factors; D029701:Saccharomyces cerevisiae Proteins; D015398:Signal Transduction; D020798:Two-Hybrid System Techniques; D020764:cdc42 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D054462:p21-Activated Kinases
D018797:Cell Cycle Proteins; D020662:Guanine Nucleotide Exchange Factors; D011993:Recombinant Fusion Proteins; D064067:Rho Guanine Nucleotide Exchange Factors; D029701:Saccharomyces cerevisiae Proteins; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; C000607459:PPM1E protein, human; C459194:PPM1F protein, human; C087358:PTC1 protein, S cerevisiae; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D000071636:Protein Phosphatase 2C; D020764:cdc42 GTP-Binding Protein