p21 activated kinase 5 activates Raf-1 and targets it to mitochondria.
Raf-1 is an important effector of Ras mediated signaling and is a critical regulator of the ERK/MAPK pathway. Raf-1 activation is controlled in part by phosphorylation on multiple residues, including an obligate phosphorylation site at serine 338. Previously PAK1 and casein kinase II have been implicated as serine 338 kinases. To identify novel kinases that phosphorylate this site, we tested the ability of group II PAKs (PAKs 4-6) to control serine 338 phosphorylation. We observed that all group II PAKs were efficient serine 338 kinases, although only PAK1 and PAK5 significantly stimulated Raf-1 kinase activity. We also showed that PAK5 forms a tight complex with Raf-1 in the cell, but not A-Raf or B-Raf. Importantly, we also demonstrated that the association of Raf-1 with PAK5 targets a subpopulation of Raf-1 to mitochondria. These data indicate that PAK5 is a potent regulator of Raf-1 activity and may control Raf-1 dependent signaling at mitochondria.
Wu
Xiaochong
X
Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, 6431 Fannin St., Houston, Texas 77030, USA.
Carr
Heather S
HS
Dan
Ippeita
I
Ruvolo
Peter P
PP
Frost
Jeffrey A
JA
D002460:Cell Line; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding; D019908:Proto-Oncogene Proteins c-raf / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism*
D010768:Phosphoserine; D004815:Epidermal Growth Factor; D019908:Proto-Oncogene Proteins c-raf; D054462:p21-Activated Kinases; D020928:Mitogen-Activated Protein Kinases