Journal article
Epidermal growth factor receptor juxtamembrane region regulates allosteric tyrosine kinase activation
Proceedings of the National Academy of Sciences - PNAS, Vol.104(49), pp.19238-19243
12/04/2007
DOI: 10.1073/pnas.0703854104
PMCID: PMC2148274
PMID: 18042729
Abstract
Structural studies of the extracellular and tyrosine kinase domains of the epidermal growth factor receptor (ErbB-1) provide considerable insight into facets of the receptor activation mechanism, but the contributions of other regions of ErbB-1 have not been ascertained. This study demonstrates that the intracellular juxtamembrane (JM) region plays a vital role in the kinase activation mechanism. In the experiments described herein, the entire ErbB-1 intracellular domain (ICD) has been expressed in mammalian cells to explore the significance of the JM region in kinase activity. Deletion of the JM region (ΔJM) results in a severe loss of ICD tyrosine phosphorylation, indicating that this region is required for maximal activity of the tyrosine kinase domain. Coexpression of ΔJM and dimerization-deficient kinase domain ICD mutants revealed that the JM region is indispensable for allosteric kinase activation and productive monomer interactions within a dimer. Studies with the intact receptor confirmed the role of the JM region in kinase activation. Within the JM region, Thr-654 is a known protein kinase C (PKC) phosphorylation site that modulates kinase activity in the context of the intact ErbB-1 receptor; yet, the mechanism is not known. Whereas a T654A mutation promotes increased ICD tyrosine phosphorylation, the phosphomimetic T654D mutant generates a 50% reduction in ICD tyrosine phosphorylation. Similar to the ΔJM mutants, the T654D mutant ICD failed to interact with a wild-type monomer. This study reveals an integral role for the intracellular JM region of ErbB-1 in allosteric kinase activation.
Details
- Title: Subtitle
- Epidermal growth factor receptor juxtamembrane region regulates allosteric tyrosine kinase activation
- Creators
- Kristina W. Thiel - Vanderbilt UniversityGraham Carpenter - Vanderbilt University School of Medicine
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.104(49), pp.19238-19243
- DOI
- 10.1073/pnas.0703854104
- PMID
- 18042729
- PMCID
- PMC2148274
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences
- Language
- English
- Date published
- 12/04/2007
- Academic Unit
- Obstetrics and Gynecology
- Record Identifier
- 9984383299302771
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