A Cdo-Bnip-2-Cdc42 signaling pathway regulates p38alpha/beta MAPK activity and myogenic differentiation.
The p38alpha/beta mitogen-activated protein kinase (MAPK) pathway promotes skeletal myogenesis, but the mechanisms by which it is activated during this process are unclear. During myoblast differentiation, the promyogenic cell surface receptor Cdo binds to the p38alpha/beta pathway scaffold protein JLP and, via JLP, p38alpha/beta itself. We report that Cdo also interacts with Bnip-2, a protein that binds the small guanosine triphosphatase (GTPase) Cdc42 and a negative regulator of Cdc42, Cdc42 GTPase-activating protein (GAP). Moreover, Bnip-2 and JLP are brought together through mutual interaction with Cdo. Gain- and loss-of-function experiments with myoblasts indicate that the Cdo-Bnip-2 interaction stimulates Cdc42 activity, which in turn promotes p38alpha/beta activity and cell differentiation. These results reveal a previously unknown linkage between a cell surface receptor and downstream modulation of Cdc42 activity. Furthermore, interaction with multiple scaffold-type proteins is a distinctive mode of cell surface receptor signaling and provides one mechanism for specificity of p38alpha/beta activation during cell differentiation.
Kang
Jong-Sun
JS
Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, NY 10029, USA. jskang@med.skku.ac.kr
Bae
Gyu-Un
GU
Yi
Min-Jeong
MJ
Yang
Youn-Joo
YJ
Oh
Ji-Eun
JE
Takaesu
Giichi
G
Zhou
Yi Ting
YT
Low
Boon Chuan
BC
Krauss
Robert S
RS
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D004789:Enzyme Activation; D017353:Gene Deletion; D006801:Humans; D051379:Mice; D024510:Muscle Development; D032446:Myoblasts / Q000166:cytology / Q000201:enzymology; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C510744:Cdon protein, mouse; D015815:Cell Adhesion Molecules; C459664:Nip21 protein, mouse; D011506:Proteins; C468928:Spag9 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases; D020764:cdc42 GTP-Binding Protein