Editors' ChoiceInflammation

Keeping TAB-1 on p38

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Science's STKE  07 Mar 2006:
Vol. 2006, Issue 325, pp. tw84
DOI: 10.1126/stke.3252006tw84

p38 mitogen-activated protein kinase (p38 MAPK) undergoes phosphorylation by upstream MAPK kinases (MKKs) in response to cellular stress and itself phosphorylates various transcription factors to activate proinflammatory genes. In an alternative pathway, TAB-1 (TAK-1-binding protein) promotes p38 autophosphorylation and activation independently of MKK signaling. Heart failure is associated with an inflammatory response, and TAB-1 activation of p38 has been identified in ischemic heart, leading Lu et al. to investigate the sequelae in cardiac tissue of p38 activation through the TAB-1 pathway. Human TAB-1 expressed in cultured rat neonatal ventricular cardiomyocytes stimulated both p38 phosphorylation and the ability of immunoprecipitated p38 to phosphorylate the transcription factor ATF2. However, unlike a constitutively active form of MKK3bE, TAB-1 failed to increase the abundance of tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), or atrial naturetic factor mRNA and protein. Indeed, coexpression of TAB-1 attenuated such sequelae of p38 activation by MKK3bE as phosphorylation of MAPK-activated protein kinase and HSP27 and increased COX-2 expression, as well as an interleukin-1β-dependent increase in COX-2 abundance. Immunoprecipitation analysis indicated that TAB-1 bound to p38; moreover, TAB-1 expression decreased association of p38 with MKK. Furthermore, immunofluorescence analysis of labeled proteins indicated that, whereas coexpressed p38 and MKK3b were present in both nucleus and cytoplasm, TAB-1 was solely cytosolic, and its coexpression with p38 led to retention of p38 in the cytoplasm as well as a decrease in overlap of cytoplasmic p38 and MKK3bE. Thus, TAB-1 appears to influence p38 localization and to inhibit its interaction with MKK and the downstream response to MKK activation of p38.

G. Lu, Y. J. Kang, J. Han, H. R. Herschman, E. Stefani, Y. Wang, TAB-1 modulates intracellular localization of p38 MAP kinase and downstream signaling. J. Biol. Chem. 281, 6087-6095 (2006). [Abstract] [Full Text]

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