STEP - A FAMILY OF BRAIN-ENRICHED PTPS - ALTERNATIVE SPLICING PRODUCES TRANSMEMBRANE, CYTOSOLIC AND TRUNCATED ISOFORMS

The family of striatal enriched phosphatases (STEPs) consists of prote in tyrosine phosphatases (PTPs) that are enriched within the central n ervous system, Previous biochemical studies have shown that the STEP f amily includes transmembrane, as well as soluble, cytosolic proteins, We now extend these findings with the isolation and characterization o f a new truncated member of this family termed STEP(38). The cDNA of S TEP(38) encodes a protein of 346 amino acids with a predicted mobility of 38 kDa, In contrast to the cytosolic variants, it contains two hyd rophobic amino acid sequences at its N-terminus, two sequences enriche d in Pro, Glu, Asp, Ser and Thr residues (PEST sequences), and two pol yproline domains, We have used differential centrifugation, continuous sucrose gradients, and transfection experiments to clarify the subcel lular localization of STEP(38) within membrane compartments. These exp eriments suggest that a pool of STEP(38) is targeted to membrane compa rtments of the endoplasmic reticulum, The STEP(38) cDNA contains a sto p codon upstream of the catalytic phosphatase domain that is normally present in other STEP variants, and enzymatic assays conform that STEP (38) is inactive, Thus, the STEP family consists of cytosolic, transme mbrane, and truncated isoforms. These findings are similar to what has been found for some members of the protein tyrosine kinase (PTK) fami ly that uses alternative splicing mechanisms to produce active and ina ctive variants, By analogy with suggested mechanisms of action for the truncated PTKs, inactive STEP isoforms may participate in signaling e vents by protecting potential substrates from dephosphorylation by oth er members of this family.