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Vol. 9, Issue 12, 3367-3382, December 1998
Department of Cell Biology and The Cell Adhesion and Matrix
Research Center, University of Alabama at Birmingham, Birmingham,
Alabama 35294-0019
Many of the protein-protein interactions that are essential
for eukaryotic intracellular signal transduction are mediated by
protein binding modules including SH2, SH3, and LIM domains. Nck is a
SH3- and SH2-containing adaptor protein implicated in coordinating
various signaling pathways, including those of growth factor receptors
and cell adhesion receptors. We report here the identification,
cloning, and characterization of a widely expressed, Nck-related
adaptor protein termed Nck-2. Nck-2 comprises primarily three
N-terminal SH3 domains and one C-terminal SH2 domain. We show that
Nck-2 interacts with PINCH, a LIM-only protein implicated in
integrin-linked kinase signaling. The PINCH-Nck-2 interaction is mediated by the fourth LIM domain of PINCH and the third SH3 domain
of Nck-2. Furthermore, we show that Nck-2 is capable of recognizing
several key components of growth factor receptor kinase-signaling pathways including EGF receptors, PDGF receptor-
, and IRS-1. The
association of Nck-2 with EGF receptors was regulated by EGF stimulation and involved largely the SH2 domain of Nck-2, although the
SH3 domains of Nck-2 also contributed to the complex formation. The
association of Nck-2 with PDGF receptor- was dependent on PDGF
activation and was mediated solely by the SH2 domain of Nck-2. Additionally, we have detected a stable association between Nck-2 and
IRS-1 that was mediated primarily via the second and third SH3 domain
of Nck-2. Thus, Nck-2 associates with PINCH and components of different
growth factor receptor-signaling pathways via distinct mechanisms.
Finally, we provide evidence indicating that a fraction of the Nck-2
and/or Nck-1 proteins are associated with the cytoskeleton. These
results identify a novel Nck-related SH2- and SH3-domain-containing protein and suggest that it may function as an adaptor protein connecting the growth factor receptor-signaling pathways with the
integrin-signaling pathways.
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