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Molecular and Cellular Biology, April 2003, p. 2298-2308, Vol. 23, No. 7
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.7.2298-2308.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

MEK Kinase 2 and the Adaptor Protein Lad Regulate Extracellular Signal-Regulated Kinase 5 Activation by Epidermal Growth Factor via Src

Weiyong Sun,1 Xudong Wei,2 Kamala Kesavan,1 Timothy P. Garrington,1 Ruihua Fan,2 Junjie Mei,3 Steven M. Anderson,4 Erwin W. Gelfand,2 and Gary L. Johnson1*

Departments of Pharmacology,1 Pathology, University of Colorado Health Sciences Center, Denver, Colorado 80262,4 Departments of Pediatrics,2 Immunology, National Jewish Medical and Research Center, Denver, Colorado 802063

Received 10 June 2002/ Returned for modification 23 July 2002/ Accepted 2 January 2003

Lad is an SH2 domain-containing adaptor protein that binds MEK kinase 2 (MEKK2), a mitogen-activated protein kinase (MAPK) kinase kinase for the extracellular signal-regulated kinase 5 (ERK5) and JNK pathways. Lad and MEKK2 are in a complex in resting cells. Antisense knockdown of Lad expression and targeted gene disruption of MEKK2 expression results in loss of epidermal growth factor (EGF) and stress stimuli-induced activation of ERK5. Activation of MEKK2 and the ERK5 pathway by EGF and stress stimuli is dependent on Src kinase activity. The Lad-binding motif is encoded within amino acids 228 to 282 in the N terminus of MEKK2, and expression of this motif blocks Lad-MEKK2 interaction, resulting in inhibition of Src-dependent activation of MEKK2 and ERK5. JNK activation by EGF is similarly inhibited by loss of Lad or MEKK2 expression and by blocking the interaction of MEKK2 and Lad. Our studies demonstrate that Src kinase activity is required for ERK5 activation in response to EGF, MEKK2 expression is required for ERK5 activation by Src, Lad and MEKK2 association is required for Src activation of ERK5, and EGF and Src stimulation of ERK5-regulated MEF2-dependent promoter activity requires a functional Lad-MEKK2 signaling complex.

* Corresponding author. Mailing address: Department of Pharmacology, C-236, University of Colorado Health Sciences Center, 4200 East Ninth Ave., Denver, CO 80262. Phone: (303) 315-1008. Fax: (303) 315-1022. E-mail: gary.johnson{at}uchsc.edu.

Molecular and Cellular Biology, April 2003, p. 2298-2308, Vol. 23, No. 7
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.7.2298-2308.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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