Novel p62dok family members, dok-4 and dok-5, are substrates of the c-Ret receptor tyrosine kinase and mediate neuronal differentiation.
Docking proteins are substrates of tyrosine kinases and function in the recruitment and assembly of specific signal transduction molecules. Here we found that p62dok family members act as substrates for the c-Ret receptor tyrosine kinase. In addition to dok-1, dok-2, and dok-3, we identified two new family members, dok-4 and dok-5, that can directly associate with Y1062 of c-Ret. Dok-4 and dok-5 constitute a subgroup of dok family members that is coexpressed with c-Ret in various neuronal tissues. Activated c-Ret promotes neurite outgrowth of PC12 cells; for this activity, Y1062 in c-Ret is essential. c-Ret/dok fusion proteins, in which Y1062 of c-Ret is deleted and replaced by the sequences of dok-4 or dok-5, induce ligand-dependent axonal outgrowth of PC12 cells, whereas a c-Ret fusion containing dok-2 sequences does not elicit this response. Dok-4 and dok-5 do not associate with rasGAP or Nck, in contrast to p62dok and dok-2. Moreover, dok-4 and dok-5 enhance c-Ret-dependent activation of mitogen-activated protein kinase. Thus, we have identified a subclass of p62dok proteins that are putative links with downstream effectors of c-Ret in neuronal differentiation.
Grimm
J
J
Max-Delbrueck-Center for Molecular Medicine, 13092 Berlin, Germany.
Sachs
M
M
Britsch
S
S
Di Cesare
S
S
Schwarz-Romond
T
T
Alitalo
K
K
Birchmeier
W
W
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D018076:DNA, Complementary / Q000235:genetics / Q000302:isolation & purification; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D004622:Embryo, Mammalian; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008969:Molecular Sequence Data; D005810:Multigene Family; D016501:Neurites / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009928:Organ Specificity; D016716:PC12 Cells; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret; D016601:RNA-Binding Proteins; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D042787:Receptor, TIE-2; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000502:physiology; D020798:Two-Hybrid System Techniques; D020703:ras GTPase-Activating Proteins / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C489560:DOK1 protein, human; C486625:DOK4 protein, human; C489561:Dok1 protein, mouse; C498444:Dok2 protein, mouse; C432911:Dok4 protein, mouse; C499010:Dok5 protein, mouse; D029721:Drosophila Proteins; C074561:GAP-associated protein p62; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D016601:RNA-Binding Proteins; D020703:ras GTPase-Activating Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; C416649:Ret protein, Drosophila; C494999:Ret protein, mouse; C495001:Ret protein, rat