Open AccessAutoregulation of the Raf-1 serine/threonine kinase
Author(s) -
Richard E. Cutler,
Robert M. Stephens,
Misty Saracino,
Deborah K. Morrison
Publication year - 1998
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.95.16.9214
Subject(s) - serine , threonine , protein kinase domain , kinase , microbiology and biotechnology , phosphorylation , biochemistry , c raf , protein kinase a , cysteine , autoregulation , chemistry , biology , mitogen activated protein kinase kinase , enzyme , mutant , gene , endocrinology , blood pressure
The Raf-1 serine/threonine kinase is a key protein involved in the transmission of many growth and developmental signals. In this report, we show that autoinhibition mediated by the noncatalytic, N-terminal regulatory region of Raf-1 is an important mechanism regulating Raf-1 function. The inhibition of the regulatory region occurs, at least in part, through binding interactions involving the cysteine-rich domain. Events that disrupt this autoinhibition, such as mutation of the cysteine-rich domain or a mutation mimicking an activating phosphorylation event (Y340D), alleviate the repression of the regulatory region and increase Raf-1 activity. Based on the striking similarites between the autoregulation of the serine/threonine kinases protein kinase C, Byr2, and Raf-1, we propose that relief of autorepression and activation at the plasma membrane is an evolutionarily conserved mechanism of kinase regulation.