p21-activated protein kinase 4 (PAK4) interacts with the keratinocyte growth factor receptor and participates in keratinocyte growth factor-mediated inhibition of oxidant-induced cell death.
Keratinocyte growth factor (KGF), a member of the fibroblast growth factor (FGF) family (also known as FGF-7), is an important protective factor for epithelial cells. The receptor for KGF (also called FGFR2-IIIb), which has intrinsic tyrosine kinase activity, is expressed specifically on epithelial cells and in the lung epithelium. Administration of KGF has been shown to protect the lung from various insults, but the mechanism of protection is not well understood. To understand the mechanism by which KGF exerts protective functions on epithelial cells, we used the yeast two-hybrid assay to identify proteins that interact with the KGF receptor (KGFR). Here we show that the cytoplasmic domain of KGFR interacts with p21-activated protein kinase (PAK) 4, which is a new member of the PAK family. The PAKs are regulated by the Rho-family GTPases Rac and Cdc42. PAK4 is the most divergent member of the PAK family of proteins and may have distinct functions. However, stimuli that regulate PAK4 activity are not known. Our data show that PAK4 can associate with the KGFR, which is dependent on KGFR tyrosine kinase activity. We show that a dominant negative mutant of PAK4 blocks KGF-mediated inhibition of caspase-3 activation in epithelial cells subjected to oxidant stress. Our data demonstrate that PAK4 is an important mediator of the anti-apoptotic effects of KGF on epithelial cells.
Lu
Yunbiao
Y
Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Pan
Zhong-Zong
ZZ
Devaux
Yvan
Y
Ray
Prabir
P
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D053148:Caspase 3; D061945:Caspase Inhibitors; D003001:Cloning, Molecular; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors / Q000502:physiology*; D051380:GRB2 Adaptor Protein; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D008969:Molecular Sequence Data; D016877:Oxidants / Q000494:pharmacology; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D011506:Proteins / Q000502:physiology; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000502:physiology*; D054462:p21-Activated Kinases
D048868:Adaptor Proteins, Signal Transducing; D061945:Caspase Inhibitors; C496453:FGF7 protein, human; C496454:Fgf7 protein, mouse; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C495949:Grb2 protein, mouse; D016877:Oxidants; D011506:Proteins; D017468:Receptors, Fibroblast Growth Factor; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D006861:Hydrogen Peroxide; D011065:Poly(ADP-ribose) Polymerases; C116367:PAK4 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2; C065104:keratinocyte growth factor receptor; C492065:Pak4 protein, mouse; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3