Cellular stress regulates the nucleocytoplasmic distribution of the protein-tyrosine phosphatase TCPTP.
Specific cellular stresses, including hyperosmotic stress, caused a dramatic but reversible cytoplasmic accumulation of the otherwise nuclear 45-kDa variant of the protein-tyrosine phosphatase TCPTP (TC45). In the cytoplasm, TC45 dephosphorylated the epidermal growth factor receptor and down-regulated the hyperosmotic stress-induced activation of the c-Jun N-terminal kinase. The hyperosmotic stress-induced nuclear exit of TC45 was not inhibited by leptomycin B, indicating that TC45 nuclear exit was independent of the exportin CRM-1. Moreover, hyperosmotic stress did not induce the cytoplasmic accumulation of a green fluorescent protein-TC45 fusion protein that was too large to diffuse across the nuclear pore. Our results indicate that TC45 nuclear exit may occur by passive diffusion and that cellular stress may induce the cytoplasmic accumulation of TC45 by inhibiting nuclear import. Neither p42(Erk2) nor the stress-activated c-Jun N-terminal kinase or p38 mediated the stress-induced redistribution of TC45. We found that only those stresses that stimulated the metabolic stress-sensing enzyme AMP-activated protein kinase (AMPK) induced the redistribution of TC45. In addition, specific pharmacological activation of the AMPK was sufficient to cause the accumulation of TC45 in the cytoplasm. Our studies indicate that specific stress-activated signaling pathways that involve the AMPK can alter the nucleocytoplasmic distribution of TC45 and thus regulate TC45 function in vivo.
Lam
M H
MH
Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia.
Michell
B J
BJ
Fodero-Tavoletti
M T
MT
Kemp
B E
BE
Tonks
N K
NK
Tiganis
T
T
D016475:3T3 Cells; D055372:AMP-Activated Protein Kinases; D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism*; D048429:Cell Size; D002478:Cells, Cultured; D003593:Cytoplasm / Q000201:enzymology; D003600:Cytosol / Q000378:metabolism; D004058:Diffusion; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D028884:Karyopherins / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism; D009997:Osmotic Pressure; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear; D015398:Signal Transduction / Q000502:physiology; D013347:Subcellular Fractions; D000097606:Exportin 1 Protein
D055372:AMP-Activated Protein Kinases; D066246:ErbB Receptors; D028884:Karyopherins; D020928:Mitogen-Activated Protein Kinases; D009097:Multienzyme Complexes; D017346:Protein Serine-Threonine Kinases; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; D017027:Protein Tyrosine Phosphatases; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein; C516649:PTPN2 protein, human; C516653:Ptpn2 protein, mouse