The insulin‐like growth factor‐1 (IGF‐1) signaling pathway plays an important role in neuronal cell differentiation. Recent studies have shown that IGF‐1 has the capacity to counteract the retraction of neuronal processes in response to inflammatory cytokines such as TNF‐α, which is a known factor for neuronal injury in the central nervous system. This event is thought to be mediated via interference of TNF‐α‐induced interaction of β1‐integrin with insulin receptor substrate‐1 (IRS‐1). Here, we demonstrate the interaction of IRS‐1 with disintegrin and metalloproteinase ADAM10 through the N‐terminal domain of IRS‐1 and that this is involved in the regulation of neurite extension and retraction by IGF‐1 and TNF‐α, respectively. PC12 cells expressing the N‐terminal domain show enhanced neurite extension after IGF‐1 treatment and reduced neurite depletion relative to control cells after TNF‐α treatment. The level of ADAM10 was found to be increased in immunohistochemical studies of HIV encephalitis clinical samples and is present with TNF‐α and TNFR1 in both astrocytes and neurons. Altogether, these observations suggest a role for ADAM10 in the mechanism for IGF1/IRS‐1 signaling pathway in sustaining the stability of neuronal processes. J. Cell. Physiol. 229: 1039–1046, 2014. © 2013 Wiley Periodicals, Inc.