Dissociation of NGF induced signal transduction from neurite elongation by expression of a mutant adaptor protein v-Crk in PC12 cells.
Expression of the adaptor protein v-Crk in PC12 cells results in sustained activation of NGF signaling pathways and augmented neuritogenesis. However, the inhibitory effect of the v-Crk SH2 domain mutant on neurite elongation does not correlate with impaired Trk A dependent signaling events or gene induction. In contrast, immunofluorescence studies and Triton X-100 extraction experiments indicate that v-Crk co-localizes with the cytoskeletal protein paxillin in the actin cytoskeleton whereas the v-Crk SH2 mutant causes aberrant aggregration of actin filaments at the growth cones. Interestingly, the neurotrophin receptor p75 in v-CrkPC12 cells also displays enhanced localization to the cytoskeleton and these cells exhibit an increased rate of NGF internalization. Together our data suggest that v-Crk might target the NGF-activated receptor signaling complex to the cytoskeleton, thereby potentiating neuritogenesis at the growth cone level. However, mutation in the v-Crk SH2 domain uncouples NGF signaling from the cytoskeletal interactions necessary for neurite elongation.
Teng
K K
KK
Division of Hematology-Oncology, Cornell University Medical College, New York, New York 10021, USA.
Courtney
J C
JC
van Bergen en Henegouwen
P
P
Birge
R B
RB
Hempstead
B L
BL
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism / Q000648:ultrastructure; D015972:Gene Expression Regulation, Neoplastic; D007527:Isoenzymes / Q000378:metabolism; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D016501:Neurites / Q000187:drug effects* / Q000648:ultrastructure; D050736:Oncogene Protein v-crk; D016716:PC12 Cells / Q000187:drug effects / Q000648:ultrastructure; D051419:Paxillin; D051966:Phospholipase C gamma; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011506:Proteins / Q000378:metabolism; D051381:Rats; D015682:Retroviridae Proteins, Oncogenic / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction / Q000187:drug effects*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D015533:Transcriptional Activation; D010738:Type C Phospholipases / Q000378:metabolism; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D003598:Cytoskeletal Proteins; D007527:Isoenzymes; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D050736:Oncogene Protein v-crk; D051419:Paxillin; D010750:Phosphoproteins; D011506:Proteins; C496063:Pxn protein, rat; D015682:Retroviridae Proteins, Oncogenic; D055765:Shc Signaling Adaptor Proteins; C528035:Shc1 protein, rat; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D010738:Type C Phospholipases; D051966:Phospholipase C gamma