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First published online December 21, 2005
doi: 10.1242/10.1242/jcs.02710

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Functional analysis of SIRP in the growth cone

Department of Cell and Developmental Biology, University of Colorado School of Medicine and University of Colorado Cancer Center, Aurora, CO 80010, USA

^* Author for correspondence (e-mail: Karl.Pfenninger{at}uchsc.edu)

Accepted 27 September 2005

The `signal regulatory protein' SIRP is an Ig superfamily, transmembrane glycoprotein with a pair of cytoplasmic domains that can bind the phosphatase SHP-2 when phosphorylated on tyrosine. SIRP is prominent in growth cones of rat cortical neurons and located, together with the tetraspanin CD81, in the growth cone periphery. SIRP is dynamically associated with Triton-X-100-sensitive, but Brij-98-resistant, lipid microdomains, which also contain CD81. Challenge of growth cones with the integrin-binding extracellular-matrix (ECM) protein, laminin, or with the growth factors, IGF-1 or BDNF, increases SIRP phosphorylation and SHP-2 binding rapidly and transiently, via Src family kinase activation; phosphorylated SIRP dissociates from the lipid microdomains. A cytoplasmic tail fragment of SIRP (cSIRP), when expressed in primary cortical neurons, also is phosphorylated and binds SHP-2. Expression of wild-type cSIRP, but not of a phosphorylation-deficient mutant, substantially decreases IGF-1-stimulated axonal growth on laminin. On poly-D-lysine and in control conditions, axonal growth is slower than on laminin, but there is no further reduction in growth rate induced by the expression of cSIRP. Thus, the effect of cSIRP on axon growth is dependent upon integrin activation by laminin. These results suggest that SIRP functions in the modulation of axonal growth by ECM molecules, such as laminin.

Key words: Growth cone, SIRP/SHPS-1, Growth factors, Laminin, Src family kinases, Growth control

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