IDENTIFICATION OF A NOVEL SIGNAL PATHWAY FOR NGF

Project Details

Description

Nerve Growth Factor (NGF) is a polypeptide growth factor that plays a
critical role in the differentiation of immature neuroblasts and the
subsequent survival of a subpopulation of mature neurons in both the
peripheral and central nervous systems. NGF initiates its effects by
binding to TrkA, a receptor type tyrosine kinase that when activated,
initiates a signal transduction cascade resulting in Ras activation and
the induction of early response genes. NGF-induced neurite outgrowth
is also accompanied by extensive re-organization of the neuronal
cytoskeleton to initiate neurite extension of neurite processes. Indeed,
while the shape of filopodia and lamella in growth cones is largely
determined by the organization of the actin cytoskeleton, little is
known about how NGF and TrkA signaling is linked to the cytoskeleton.
Over the past few years, we have been studying the Crk adaptor protein
and its role during NGF-induced neuronal differentiation. Upon NGF
addition to PC12 cells or primary dorsal root ganglia neurons, c-Crk is
rapidly tyrosine phosphorylated at tyrosine 222. Interestingly,
overexpression of mutant c-Crk carrying a mutation at Y222 (c-CrkY222F)
impairs NGF-mediated neurite outgrowth in PC12 cells and abolishes TrkA-
induced tyrosine phosphorylation of the cytoskeletal protein Paxillin.
Our results indicate that Crk is involved in a novel aspect of TrkA
signaling to adhesion complexes, thereby regulating actin re-
organization and cell adhesion. In the present application, we shall
study the molecular mechanisms by which c-Crk couples the TrkA receptor
to the cytoskeleton, with the long-term goal to understand how NGF
promotes differentiation and survival. Specifically, we plan to: (i)
determine whether c-CrkY222F is a dominant negative c-Crk protein by
impairing NGF-induced cell adhesion, (ii) determine the circuitry
involved in NGF-induced tyrosine phosphorylation of c-Crk, (iii)
determine the relationship between NGF- and adhesion-induced tyrosine
phosphorylation of the c-Crk effector protein Paxillin, (iv) determine
the biological role of Paxillin during NGF-mediated responses, and (v)
determine the role of c-Crk during neuronal development using transgene
approaches.
StatusFinished
Effective start/end date1/1/9912/31/03

Funding

  • National Institute of General Medical Sciences: $96,870.00
  • National Institute of General Medical Sciences
  • National Institute of General Medical Sciences: $276,383.00
  • National Institute of General Medical Sciences: $153,750.00
  • National Institute of General Medical Sciences: $266,507.00
  • National Institute of General Medical Sciences: $268,423.00

ASJC

  • Cell Biology

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