Function
Pleiotrophin is a secreted growth factor that exerts its signaling through cell-surface proteoglycan and non-proteoglycan receptors. It binds to cell-surface proteoglycan receptors via their chondroitin sulfate (CS) groups, thereby regulating a wide range of cellular processes including proliferation, survival, growth, differentiation, and migration in various tissues, notably neurons and bone. It also plays a crucial role in synaptic plasticity and learning-related behavior by inhibiting long-term synaptic potentiation.
Pleiotrophin binds to PTPRZ1, neutralizing the negative charges of the CS chains of PTPRZ1, inducing PTPRZ1 clustering, and consequently leading to dimerization and inactivation of its phosphatase activity. This inactivation results in increased tyrosine phosphorylation of PTPRZ1 substrates, including ALK, CTNNB1, or AFAP1L2, ultimately activating the PI3K-AKT pathway. Through PTPRZ1 binding, Pleiotrophin controls oligodendrocyte precursor cell differentiation by enhancing AFAP1L2 phosphorylation, thereby activating the PI3K-AKT pathway.
Pleiotrophin forms a complex with PTPRZ1 and integrin alpha-V/beta-3 (ITGAV:ITGB3), stimulating endothelial cell migration through SRC dephosphorylation and activation, which subsequently leads to ITGB3 'Tyr-773' phosphorylation. In the adult hippocampus, Pleiotrophin promotes dendritic arborization, spine development, and functional integration and connectivity of newborn granule neurons through ALK by activating the AKT signaling pathway. It binds to GPC2 and chondroitin sulfate proteoglycans (CSPGs) on the neuron surface, abrogating the binding between PTPRS and CSPGs and promoting neurite outgrowth. Pleiotrophin also binds to SDC3, mediating bone formation by recruiting and attaching osteoblasts/osteoblast precursors to the sites of new bone deposition.
Pleiotrophin binds to ALK and promotes cell survival and proliferation through MAPK pathway activation. It inhibits proliferation and enhances differentiation of neural stem cells by suppressing FGF2-induced fibroblast growth factor receptor signaling pathway. Pleiotrophin mediates regulatory mechanisms in normal hemostasis and hematopoietic regeneration, maintaining the balance of myeloid and lymphoid regeneration. Additionally, Pleiotrophin may play a role in the female reproductive system, auditory response, and the progesterone-induced decidualization pathway.