The adaptor protein Nck1 mediates endothelin A receptor-regulated cell migration through the Cdc42-dependent c-Jun N-terminal kinase pathway.
Cell migration plays key roles in physiological and pathological phenomena, such as development and oncogenesis. The adaptor proteins Grb2, CrkII, and Nck1 are composed of only a single Src homology 2 domain and some Src homology 3 domains, giving specificity to each signal transduction pathway. However, little is known about the relationships between their adaptor proteins and cell migration, which are regulated by the G protein-coupled receptor. Here we showed that Nck1, but not Grb2 or CrkII, mediated the inhibition of cell migration induced by the endothelin-1 and endothelin A receptor. The small interference RNA and dominant negative mutants of Nck1 diminished the endothelin-1-induced inhibition of cell migration. Although overexpression of wild-type Nck1 was detected in the cytosol and did not affect cell migration, expression of the myristoylation signal sequence-conjugated Nck1 was detected in the membrane and induced activation of Cdc42 and c-Jun N-terminal kinase, inhibiting cell migration. Taken together, these results suggest that the endothelin A receptor transduces the signal of inhibition of cell migration through Cdc42-dependent c-Jun N-terminal kinase activation by using Nck1.
Miyamoto
Yuki
Y
Department of Cell Biology, Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0192, Japan.
Yamauchi
Junji
J
Mizuno
Norikazu
N
Itoh
Hiroshi
H
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D003600:Cytosol / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism*; D004789:Enzyme Activation; D005799:Genes, Dominant; D006801:Humans; D015151:Immunoblotting; D048031:JNK Mitogen-Activated Protein Kinases; D020935:MAP Kinase Signaling System; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D015513:Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*; D018909:src Homology Domains; D019061:src-Family Kinases / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D019332:Endothelin-1; C078332:Nck protein; D015513:Oncogene Proteins; D034741:RNA, Small Interfering; D044022:Receptor, Endothelin A; D019061:src-Family Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020764:cdc42 GTP-Binding Protein