Angiotensin II stimulated transcription of cyclooxygenase II is regulated by a novel kinase cascade involving Pyk2, MEKK4 and annexin II.

Although it is known that MEKK4 regulates MKK6, and p38 MAP kinase, extracellular stimuli that activate the serine/threonine kinase, MEKK4, are unknown. The aim of this study was then to identify stimuli that regulate MEKK4. By using recombinant MEKK4, as bait to attract interacting proteins, the calcium binding protein, annexin II, was identified by mass spectrometry as interacting with MEKK4, suggesting that MEKK4 might be regulated by calcium.

Interferon-gamma-dependent tyrosine phosphorylation of MEKK4 via Pyk2 is regulated by annexin II and SHP2 in keratinocytes.

IFNgamma (interferon-gamma) binding to its cognate receptor results, through JAK (Janus kinase), in direct activation of receptor-bound STAT1 (signal transducer and activator of transcription 1), although there is evidence for additional activation of a MAPK (mitogen-activated protein kinase) pathway. In the present paper, we report IFNgamma-dependent activation of the MEKK4 (MAPK/extracellular-signal-regulated kinase kinase kinase 4) pathway in HaCaT human keratinocytes. MEKK4 is tyrosine-phosphorylated and the IFNgamma-dependent phosphorylation requires intracellular calcium.