The signal regulatory protein' SIRPalpha is an Ig superfamily, transmembrane glycoprotein with a pair of cytoplasmic domains that can bind the phosphatase SHP-2 when phosphorylated on tyrosine. SIRPalpha is prominent in growth cones of rat cortical neurons and located, together with the tetraspanin CD81, in the growth cone periphery. SIRPalpha 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 SIRPalpha phosphorylation and SHP-2 binding rapidly and transiently, via Src family kinase activation; phosphorylated SIRPalpha dissociates from the lipid microdomains. A cytoplasmic tail fragment of SIRPalpha (cSIRPalpha), when expressed in primary cortical neurons, also is phosphorylated and binds SHP-2. Expression of wild-type cSIRPalpha, 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 cSIRPalpha. Thus, the effect of cSIRPalpha on axon growth is dependent upon integrin activation by laminin. These results suggest that SIRPalpha functions in the modulation of axonal growth by ECM molecules, such as laminin.