This study investigated the regulation of 14-3-3β binding to PTPIP51 by the tyrosine phosphorylation status of PTPIP51. The tyrosine 176 residue is phosphorylated by c-Src. Up to now, nothing is known about the impact of such well-established phosphorylation events on the interaction profile of PTPIP51 with its partners of the mitogen-activated protein kinase (MAPK) pathway. In human keratinocytes the PTPIP51 phosphorylation was varied by inhibiting the phosphatase activity, thus enhancing the phosphorylation of PTPIP51. Differential blocking of Src kinase family members (despite c-Src) by PP2 increased the activity of c-Src and the tyrosine phosphorylation of PTPIP51 at position 176, which is the substrate of c-Src kinase. The amount of PTPIP51 interactions with 14-3-3β, Raf-1, PTP1B and c-Src was evaluated and the resulting data were compared to an untreated control group. The increased phosphorylation level resulted in a sharp drop of the 14-3-3β/PTPIP51 and 14-3-3β/Raf-1 interaction. Besides the 14-3-3 interaction of PTPIP51, the interaction with the two MAPK modulators, protein kinase A (PKA) and diacylglycerol kinase alpha (DAGKα), are also regulated by the tyrosine phosphorylation status of PTPIP51. Additional immunostaining experiments were done investigating the functional implication on these interactions of the phosphorylation in apoptotic processes. In the pervanadate- and PP2-treated HaCaT cells, higher amounts of apoptotic cells were not detected as compared to the control group. The presented data confirms a tyrosine phosphorylation-dependent interaction of PTPIP51 with 14-3-3β and Raf-1 in vivo and a tyrosine-dependent interaction profile with DAGKα and PKA. The non-interaction of PTPIP51 with 14-3-3 is not sufficient for triggering apoptosis.

Protein tyrosine phosphatase interacting protein 51 (PTPIP51) interacts both in vitro and in vivo with PTP1B, a protein tyrosine phosphatase involved in cellular regulation. PTPIP51 is known to be expressed in many different types of tissues. It is involved in cellular processes such as proliferation, differentiation and apoptosis. Nevertheless, the exact cellular function of PTPIP51 is still unknown. The present review summarizes our current knowledge of the PTPIP51 gene and its mRNA and protein structure.

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PTPIP51 is expressed in adipose tissue of humans, rats and mice. Obesity with enhanced insulin resistance resulted in a reduction of PTPIP51 levels in adipocytes and influenced the interactions with PTP1B and 14-3-3β. The interaction of PTPIP51 with PTP1B suggests a regulatory function of PTPIP51 in insulin receptor signal transduction. The interaction of PTPIP51 with 14-3-3β, especially in trained individuals, hints to an involvement of PTPIP51 in the downstream regulation of insulin action.

Aims. Our previous experiments revealed an association of PTPIP51 (protein tyrosine phosphatase interacting protein 51) with the insulin signalling pathway through PTP1B and 14-3-3beta. We aimed to clarify the role of PTPIP51 in adipocyte metabolism. Methods. Four groups of ten C57Bl/6 mice each were used. Two groups were fed a standard diet; two groups were fed a high-fat diet. Two groups (one high-fat diet and one standard diet) were submitted to endurance training, while the remaining two groups served as untrained control groups. After ten weeks, we measured glucose tolerance of the mice. Adipose tissue samples were analyzed by immunofluorescence and Duolink proximity ligation assay to quantify interactions of PTPIP51 with either insulin receptor (IR) or PKA. Results. PTPIP51 and the IR and PTPIP51 and PKA, respectively, were colocalized in all groups. Standard diet animals that were submitted to endurance training showed low PTPIP51-IR and PTPIP51-PKA interactions. The interaction levels of both the IR and PKA differed between the feeding and training groups. Conclusion. PTPIP51 might serve as a linking protein in adipocyte metabolism by connecting the IR-triggered lipogenesis with the PKA-dependent lipolysis. PTPIP51 interacts with both proteins, therefore being a potential gateway for the cooperation of both pathways.