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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2006.05.013 Byline: Xuewu Zhang (1), Jodi Gureasko (1), Kui Shen (3), Philip A. Cole (3), John Kuriyan (1)(2) Abstract: The mechanism by which the epidermal growth factor receptor (EGFR) is activated upon dimerization has eluded definition. We find that the EGFR kinase domain can be activated by increasing its local concentration or by mutating a leucine (L834R) in the activation loop, the phosphorylation of which is not required for activation. This suggests that the kinase domain is intrinsically autoinhibited, and an intermolecular interaction promotes its activation. Using further mutational analysis and crystallography we demonstrate that the autoinhibited conformation of the EGFR kinase domain resembles that of Src and cyclin-dependent kinases (CDKs). EGFR activation results from the formation of an asymmetric dimer in which the C-terminal lobe of one kinase domain plays a role analogous to that of cyclin in activated CDK/cyclin complexes. The CDK/cyclin-like complex formed by two kinase domains thus explains the activation of EGFR-family receptors by homo- or heterodimerization. Author Affiliation: (1) Department of Molecular and Cell Biology and Department of Chemistry and Howard Hughes Medical Institute, University of California, Berkeley, CA 94720, USA (2) Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA (3) Department of Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA Article History: Received 27 March 2006; Revised 24 April 2006; Accepted 2 May 2006 Article Note: (miscellaneous) Published: June 15, 2006