Activation of the SAPK pathway by the human STE20 homologue germinal centre kinase

Pombo, Celia M.
Kehrl, John H.
Sanchez, Irma
Katz, Paul
Avruch, Joseph
Zon, Leonard I.
Woodgett, James R.
Force, Thomas
Kyriakis, John M.

Diabetes Research Laboratory and (Pombo, Force) Cardiology Unit, Massachusetts General Hospital East and Department of Medicine, Harvard Medical School, 149 13th Street, Charlestown, Massachusetts 02129, USA.
(Kehrl) Laboratory of Immunoregulation, NIAID, National Institutes of Health, Building 10, 10 Center Drive MSC 1876, Bethesda, Maryland 20892, USA.
(Katz) Department of Medicine, Georgetown University Medical Center, Washington, DC 20007, USA.
(Zon) Howard Hughes Medical Institute and Division of Hematology/Oncology, Children's Hospital and Dana Farber Cancer Institute, Harvard Medical School, Enders 650, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.
(Woodgett) Ontario Cancer Institute, Princess Margaret Hospital, 500 Sherbourne Street, Toronto, Ontario M4X 1K9, Canada.
(Kyriakis) To whom correspondence should be addressed.

Nature 377(6551):p 750-754, October 26, 1995.

EUKARYOTIC cells respond to different extracellular stimuli by recruiting homologous signalling pathways that use members of the MEKK, MEK and ERK families of protein kinases. The MEKK-->MEK-->ERK core pathways of Saccharomyces cerevisiae may themselves be regulated by members of the STE20 family of protein kinases . Here we report specific activation of the mammalian stress-activated protein kinase (SAPK) pathway by germinal centre kinase (GCK; ), a human STE20 homologue . SAPKs, members of the ERK family, are activated in situ by inflammatory stimuli, including tumour-necrosis factor (TNF) and interleukin-1, and phosphorylate and probably stimulate the transactivation function of c-Jun . Although GCK is found in many tissues, its expression in lymphoid follicles is restricted to the cells of the germinal centre, where it may participate in B-cell differentiation . Activation of the SAPK pathway by GCK illustrates further the striking conservation of eukaryotic signalling mechanisms and defines the first physiological function of a mammalian Ste20.