A kinase-negative epidermal growth factor receptor that retains the capacity of stimulate DNA synthesis

Coker, Kenneth J.; Staros, James V.; Guyer, Cheryl A.

doi:10.1016/0962-8924(94)90049-3

Cited by 2 publications

(2 citation statements)

References 30 publications

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“…The problems associated with functional redundancy of growth factor receptors are inevitably complicated even further by the well established but widely ignored observation that kinase‐dead EGF receptor is capable of intracellular signaling, apparently by dimerization with other receptors or kinases [Coker et al, 1994; Wright et al, 1995]. Thus, it is not even certain that an “essential” target (as determined with knockout or dominant‐negative methodologies) would be a useful target for a small molecule catalytic inhibitor.…”

Section: Progression To Hormone “Independence”mentioning

confidence: 99%

Ras signaling in prostate cancer progression

Weber¹,

Gioeli²

2003

J of Cellular Biochemistry

137

110

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When prostate cancer is first detected it generally is dependent on the presence of androgens for growth, and responds to androgen ablation therapies. However, the disease often recurs in a disseminated and apparently androgen independent (AI) form, and in this state is almost invariably fatal. Considerable evidence indicates that the Androgen receptor (AR) continues to be required even in androgen independent (AI) disease. Thus, a key to understanding hormone independent prostate cancer is to determine the mechanism(s) by which the AR can function even in the absence of physiologic levels of androgen. In this article, we argue that growth factors and receptors that utilize Ras family members drive prostate cancer progression to a state of androgen hypersensitivity; and that post-translational modifications (e.g., phosphorylations) of transcriptional cofactors might be responsible for modulating the function of the AR so that it is active even at low concentrations of androgen.

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Section: Progression To Hormone “Independence”mentioning

confidence: 99%

Ras signaling in prostate cancer progression

Weber¹,

Gioeli²

2003

J of Cellular Biochemistry

137

110

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“…The first question can be addressed in part by structure-function studies with EGF-R mutants, in which particular regions/subdomains have been selectively altered (Coker et al, 1994;Gotoh et al, 1994;Soler et al, 1994). The first question can be addressed in part by structure-function studies with EGF-R mutants, in which particular regions/subdomains have been selectively altered (Coker et al, 1994;Gotoh et al, 1994;Soler et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Biochemical characterization of mutant EGF receptors expressed in the hemopoietic cell line BaF/3

Walker

Hibbs

et al. 1998

Growth Factors

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The Epidermal Growth Factor (EGF) receptor appears to require a fully active tyrosine kinase domain to transmit mitogenic signals. However, waved-2 mice carrying a mutation in the alpha-helix C of their EGF-R, which abolishes tyrosine kinase activity, only display a mild phenotype and are fully viable. This suggests that the mutant EGF-R signals through heterodimerization with endogenous, kinase active members of the EGF-R family such as ErbB-2 or ErbB-4. We have examined the biochemistry of EGF-Rs carrying mutations in the alpha-helix C of the human EGF-R (V741G and Y740F), in the ATP binding site (K721R) and at the C-terminus (CT957), by expression in BaF/3 cells which are devoid of EGF-R family members. The in vitro kinase activity of the alpha-helix C EGF-R mutants was severely impaired as a result of reduced phosphotransfer activity without appreciable changes in the affinity for either ATP or peptide substrate. Surprisingly, EGF stimulation of cells carrying the different mutant or wild type EGF-Rs resulted in tyrosine phosphorylation of EGF-R proteins; this phosphorylation was abolished in crude plasma membrane preparations, and appears to be due to activation of a membrane-associated or a cytosolic kinase. Receptor-mediated internalization of EGF was profoundly suppressed in the V741G, K721R and CT957 receptor mutant, and high affinity EGF binding was undetectable in the V741G and K721R receptors. We conclude that specific residues in the C-helix of the EGF-R kinase are essential for full kinase activity; mutations in this region do not affect ATP binding, but impair the receptors' phosphotransfer ability. High affinity binding of EGF is not dependent on tyrosine kinase activity or sequences in the C-terminus.

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A kinase-negative epidermal growth factor receptor that retains the capacity of stimulate DNA synthesis

Cited by 2 publications

References 30 publications

Ras signaling in prostate cancer progression

Ras signaling in prostate cancer progression

Biochemical characterization of mutant EGF receptors expressed in the hemopoietic cell line BaF/3

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