New paradigms for the function of JNKK1/MKK4 in controlling growth of disseminated cancer cells.
Much work has been done in the 20 years since the discovery of the first metastasis suppressor gene to investigate the diverse biochemical functions of the proteins these genes encode. The function of metastasis suppressors cannot be solely predicted from correlative clinical data or in vitro studies. Instead, careful design of in vivo experiments to test broader hypotheses is necessary to pinpoint the mechanism of action of these novel proteins. Our laboratory identified c-Jun NH2-terminal kinase activating kinase 1 (JNKK1)/Mitogen-activated protein kinase (MAPK) kinase 4 (JNKK1/MKK4) as a metastasis suppressor in prostate and ovarian cancer. JNKK1/MKK4 is a stress activated protein kinase (SAPK) involved in a variety of signaling events, ranging from the regulation of hepatoblast survival during mammalian development to metastasis suppression in adult ovarian and prostate cancers. JNKK1/MKK4 function has typically been associated with the c-Jun NH2-terminal kinase (JNK) signaling pathway, particularly in the immune system where JNK plays a role in inflammatory signaling and apoptosis. However, evidence continues to accumulate that JNKK1/MKK4 is also a physiologic activator of p38 under certain conditions, and that activation of p38 arrests cell cycle progression. This review will provide a historical perspective on the role of JNKK1/MKK4 in SAPK signaling, including some recent findings from our own laboratory that shed light on the complicated role for JNKK1/MKK4 in metastatic colonization.
Committee on Cancer Biology, The University of Chicago, 5841 South Maryland Avenue, MC6038, Chicago, IL 60637, United States.
Jennifer L
JL
Taylor
Russell Z
RZ
Szmulewitz
Tamara
T
Lotan
Jonathan
J
Hickson
Donald Vander
DV
Griend
Seiko Diane
SD
Yamada
Kay
K
Macleod
Carrie W
CW
Rinker-Schaeffer
D002453:Cell Cycle; D016923:Cell Death; D002455:Cell Division; D006706:Homeostasis; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D009362:Neoplasm Metastasis / Q000517:prevention & control; D009369:Neoplasms / Q000473:pathology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D025521:Tumor Suppressor Proteins; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human