Sap-1/PTPRH activity is regulated by reversible dimerization.
Sap-1/PTPRH, a receptor protein tyrosine phosphatase (RPTP), is a ubiquitously expressed enzyme that is upregulated in human gastrointestinal cancers. Using both chemical cross-linkers and co-immunoprecipitation we show that overexpressed full-length Sap-1 is present as a stable homodimer. Unlike a number of adhesion RPTPs which have tandem catalytic domains that are involved in dimerization, Sap-1 has a single catalytic domain, and we show that this domain is not required for Sap-1 dimerization, which is mediated instead by the large extracellular and transmembrane domains. Exposing cells that express the receptor to a reducing environment reversibly disrupts the Sap-1 dimer, suggesting that cysteine bonds play a role in dimer formation/stabilization. The switch between Sap-1 dimers and monomers is accompanied by an increase in catalytic activity as judged by its capacity to dephosphorylate and activate c-src, which we identify as a novel substrate for this phosphatase.
Wälchli
Sébastien
S
Serono Pharmaceutical Research Institute, 14, chemin des Aulx, Plan-les-Ouates/Geneva, Switzerland.
Espanel
Xavier
X
Hooft van Huijsduijnen
Rob
R
D000818:Animals; D019556:COS Cells; D020134:Catalytic Domain; D003432:Cross-Linking Reagents / Q000737:chemistry / Q000378:metabolism; D003545:Cysteine / Q000235:genetics / Q000378:metabolism; D019281:Dimerization; D015870:Gene Expression; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion / Q000235:genetics; D013329:Structure-Activity Relationship
D003432:Cross-Linking Reagents; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D017027:Protein Tyrosine Phosphatases; D003545:Cysteine