Inhibition of protein tyrosine phosphatases (PTPs) counterbalancing protein tyrosine kinases (PTKs) offers a strategy for augmenting PTK actions. Conservation of PTP catalytic sites limits development of specific PTP inhibitors. A number of receptor PTPs, including the leukocyte common antigen (LAR) and PTPµ, contain a wedge-shaped helix-loop-helix (HLH) located near the first catalytic domain. HLH domains in other proteins demonstrate homophilic binding and inhibit function; therefore, we tested the hypothesis that LAR wedge domain peptides would exhibit homophilic binding, bind to LAR and inhibit LAR function. Fluorescent beads coated with LAR or PTPµ wedge peptides demonstrated PTP-specific homophilic binding and LAR wedge peptide-coated beads precipitated LAR protein. Administration of LAR wedge Tat-peptide to PC12 cells resulted in increased proliferation, decreased cell death, increased neurite outgrowth and augmented Trk PTK-mediated responses to NGF, a phenotype matching that found in PC12 cells with reduced LAR levels. PTPµ wedge Tat-peptide had no effect on PC12 cells but blocked the PTPµ-dependent phenotype of neurite outgrowth of retinal ganglion neurons on a PTPµ substrate while LAR wedge peptide had no effect. The survival- and neurite-promoting effect of the LAR wedge peptide was blocked by the Trk inhibitor K252a and reciprocal co-immunoprecipitation demonstrated LAR/TrkA association. Addition of LAR wedge peptide inhibited LAR co-immunoprecipitation with TrkA, augmented NGF-induced activation of TrkA, ERK and AKT and in the absence of exogenous NGF induced activation of TrkA, ERK and AKT. PTP wedge domain peptides provide a unique PTP inhibition strategy and offer a novel approach for augmenting PTK function.