Increasing evidence indicates a role of insulin signalling for insulin secretion from the pancreatic P-cells. Therefore, regulators of insulin signalling, like protein tyrosine phosphatases, could also have an impact on insulin secretion. Here, we investigated a possible role of the negative regulator protein tyrosine phosphatase alpha (PTPalpha) for insulin secretion. RT-PCR analysis confirmed that both splice variants of the extracellular domain of PTPalpha that vary by an insert of 9 amino acids are expressed in human islets and insulinoma cells (INS-1E, RIN1046-38). Overexpression of the wild type PTPalpha splice variant containing the 9 amino acids reduced insulin secretion, as did a mutant form unable to bind Grb2 (Tyr798Phe). By contrast, overexpression of a phosphatase inactive mutant improved insulin secretion. These data reveal a functional relevance of PTPalpha for insulin secretion. (C) 2003 Elsevier Inc. All rights reserved.