Protein tyrosine phosphatase receptor type Z (PTPRZ) maintains oligodendrocyte precursor cells (OPCs) in an undifferentiated state. The inhibition of PTPase by its ligand pleiotrophin (PTN) promotes OPC differentiation; however, the substrate molecules of PTPRZ involved in the differentiation have not yet been elucidated in detail. We herein demonstrated that the tyrosine phosphorylation of AFAP1L2, paxillin, ERBB4, GIT1, p190RhoGAP, and NYAP2 was enhanced in OPC‐like OL1 cells by a treatment with PTN. AFAP1L2, an adaptor protein involved in the PI3K‐AKT pathway, exhibited the strongest response to PTN. PTPRZ dephosphorylated AFAP1L2 at tyrosine residues in vitro and in HEK293T cells. In OL1 cells, the knockdown of AFAP1L2 or application of a PI3K inhibitor suppressed cell differentiation as well as the PTN‐induced phosphorylation of AKT and mTOR. We generated a knock‐in mouse harboring a catalytically inactive Cys to Ser (CS) mutation in the PTPase domain. The phosphorylation levels of AFAP1L2, AKT, and mTOR were higher, and the expression of oligodendrocyte markers, including myelin basic protein (MBP) and myelin regulatory factor (MYRF), was stronger in CS knock‐in brains than in wild‐type brains on postnatal day 10; however, these differences mostly disappeared in the adult stage. Adult CS knock‐in mice exhibited earlier remyelination after cuprizone‐induced demyelination through the accelerated differentiation of OPCs. These phenotypes in CS knock‐in mice were similar to those in Ptprz‐deficient mice. Therefore, we conclude that the PTN‐PTPRZ signal stimulates OPC differentiation partly by enhancing the tyrosine phosphorylation of AFAP1L2 in order to activate the PI3K‐AKT pathway.