Abstract
Reversible phosphorylation is a fundamental regulatory mechanism, intricately coordinated by kinases and phosphatases, two classes of enzymes widely disrupted in human disease. To better understand the functions of the relatively understudied phosphatases, we have used complementary affinity purification and proximity-based interaction proteomics approaches to generate a physical interactome for 140 human proteins harboring phosphatase catalytic domains. We identified 1,335 high-confidence interactions (1,104 previously unreported), implicating these phosphatases in the regulation of a variety of cellular processes. Systematic phenotypic profiling of phosphatase catalytic and regulatory subunits revealed that phosphatases from every evolutionary family impinge on mitosis. Using clues from the interactome, we have uncovered unsuspected roles for DUSP19 in mitotic exit, CDC14A in regulating microtubule integrity, PTPRF in mitotic retraction fiber integrity, and DUSP23 in centriole duplication. The functional phosphatase interactome further provides a rich resource for ascribing functions for this important class of enzymes.
Highlights
Reversible protein phosphorylation, catalyzed by the reciprocal actions of kinases and phosphatases, is a ubiquitous signal transduction mechanism, central to the regulation of many biological processes
Serine and threonine residues are mainly dephosphorylated by phosphoprotein phosphatase (PPP) family phosphatases, including PP1 and PP2A, and metallo-dependent protein phosphatases (PPM, known as PP2C)
Interaction Networks Reveal a Role for Phosphatases in a Variety of Cellular Processes Many phosphatases are regulated though protein-protein interactions
Summary
Reversible protein phosphorylation, catalyzed by the reciprocal actions of kinases and phosphatases, is a ubiquitous signal transduction mechanism, central to the regulation of many biological processes. There are $150 genes in the human genome encoding proteins containing domains consistent with protein dephosphorylation (reviewed in Duan et al, 2015) This capability evolved independently on at least four occasions, resulting in families with unique catalytic mechanisms and varied substrate specificity (reviewed in Moorhead et al, 2009). Serine and threonine residues are mainly dephosphorylated by phosphoprotein phosphatase (PPP) family phosphatases, including PP1 and PP2A, and metallo-dependent protein phosphatases (PPM, known as PP2C). These families diverge in sequence but converge structurally at the catalytic center (Das et al, 1996). This family includes the receptor and nonreceptor PTPs and the dual-specificity phosphatases (DSPs) that can dephosphorylate both tyrosine and serine/threonine residues, and in some cases, nonprotein substrates, including phospholipids (reviewed in Alonso and Pulido, 2016)
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