A point mutation at the ATP-binding site of the EGF-receptor abolishes signal transduction.

Moolenaar, Wouter H.; Bierman, A. J.; Tilly, Ben C.; Verlaan, Ingrid; Defize, L. H. K.; Honegger, A M; Ullrich, Axel; Schlessinger, Joseph

doi:10.1002/j.1460-2075.1988.tb02866.x

Cited by 207 publications

(86 citation statements)

References 21 publications

(14 reference statements)

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“…Furthermore, introducing a kinasenegative point mutation (K623A or Y823F) on top of class II JM domain mutant V560D prolonged its half-life from <1 h to >2 h (Fig. S3), further confirming that receptor degradation is dependent upon tyrosine kinase activity (28)(29)(30).…”

Section: Tunicamycin (mentioning

confidence: 63%

Distinct cellular properties of oncogenic KIT receptor tyrosine kinase mutants enable alternative courses of cancer cell inhibition

Shi

Sousa

Mandel-Bausch³

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Large genomic sequencing analysis as part of precision medicine efforts revealed numerous activating mutations in receptor tyrosine kinases, including KIT. Unfortunately, a single approach is not effective for inhibiting cancer cells or treating cancers driven by all known oncogenic KIT mutants. Here, we show that each of the six major KIT oncogenic mutants exhibits different enzymatic, cellular, and dynamic properties and responds distinctly to different KIT inhibitors. One class of KIT mutants responded well to anti-KIT antibody treatment alone or in combination with a low dose of tyrosine kinase inhibitors (TKIs). A second class of KIT mutants, including a mutant resistant to imatinib treatment, responded well to a combination of TKI with anti-KIT antibodies or to anti-KIT toxin conjugates, respectively. We conclude that the preferred choice of precision medicine treatments for cancers driven by activated KIT and other RTKs may rely on clear understanding of the dynamic properties of oncogenic mutants. T he rapid growth in large cancer-sequencing efforts using exome and genome sequencing, as well as elucidation of copy number variations of many cancers, has provided important information about the genetic landscapes and somatic mutations that occur in most cancers. The various catalogs of somatic mutations, chromosomal translocations, and aberrant gene expressions have provided valuable insights about distinct patient populations exhibiting gain-of-function mutations that function as causal "driver" genes for subtypes of different cancers (1-3). These studies have revealed numerous oncogenic mutations in receptor tyrosine kinases (RTKs), which result in constitutive ligand-independent tyrosine kinase activation, cell transformation, and oncogenesis. Consequently, more than 20 kinase inhibitors and half a dozen therapeutic antibodies that block the action of RTKs or the action of critical components of their intracellular signaling pathways have been developed during the past decade and successfully applied in the clinic for treatment of many cancers.A variety of gain-of-function somatic mutations in the receptor tyrosine kinase KIT, including point mutations, in-frame deletions, and in-frame duplications, have been identified in human cancers, including gastro-intestinal-stromal tumors (GISTs), acute myeloid leukemia (AML), mast cell leukemia (MCL), and melanomas (4). Activation of the receptor tyrosine kinase KIT by its ligand stem cell factor (SCF) plays a central role in development of germ cells, hematopoietic cells, interstitial pacemaker cells, and other cells (5). Like other members of the type ΙΙΙ family of RTKs, the extracellular ligand binding domain of KIT contains five Ig-like modules (designated as D1, D2, D3, D4, and D5) connected to a single transmembrane helix, followed by a cytoplasmic region containing a regulatory juxtamembrane (JM) domain, a tyrosine kinase domain (TKD) with a kinase insert region and a C-terminal tail. Tyrosine autophosphorylation sites in the kinase insert region and the...

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Section: Tunicamycin (mentioning

confidence: 63%

Distinct cellular properties of oncogenic KIT receptor tyrosine kinase mutants enable alternative courses of cancer cell inhibition

Shi

Sousa

Mandel-Bausch³

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…It has been well established that activation of such kinase activity following ligand binding is essential for the generation of intracellular second messengers and the subsequent control of cell proliferation (2). However, it is becoming more and more clear that the biological response of a ligand is not a mere reflection of its receptor binding properties, but the result of a complex interplay between receptor and ligand molecules both at the cell surface and inside the cell.…”

Section: Introductionmentioning

confidence: 99%

Superagonistic activation of ErbB-1 by EGF-related growth factors with enhanced association and dissociation rate constants

Lenferink

Zoelen

Vugt

et al. 2000

Journal of Biological Chemistry

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“…The requirement for the EGFR tyrosine kinase activity in cellular signaling is based upon observations that receptors in which Lys-721 within the ATP binding site has been mutated and, hence, lack detectable kinase activity, do not display the full range of biochemical responses (13)(14)(15). This apparent requirement for kinase activity has focused attention on the development of drugs capable of blocking kinase activity specifically.…”

mentioning

confidence: 99%

Unliganded Epidermal Growth Factor Receptor Dimerization Induced by Direct Interaction of Quinazolines with the ATP Binding Site

Arteaga¹,

Ramsey²,

Shawver³

et al. 1997

Journal of Biological Chemistry

131

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(11,12), suggesting a more than passive role of the IC domain in dimerization.The requirement for the EGFR tyrosine kinase activity in cellular signaling is based upon observations that receptors in which Lys-721 within the ATP binding site has been mutated and, hence, lack detectable kinase activity, do not display the full range of biochemical responses (13-15). This apparent requirement for kinase activity has focused attention on the development of drugs capable of blocking kinase activity specifically. Quinazoline inhibitors of the EGFR kinase are competitive with ATP; in the 1-10 nM range, they block EGFR phosphorylation and Src kinase activity in vivo but do not inhibit the platelet-derived growth factor receptor, p210Bcr-Abl , insulin receptor, CSF-1 receptor, and bFGF receptor tyrosine kinases (16 -19). In studying the ability of the EGFR kinase quinazoline inhibitors AG-1478 and AG-1517 to block TGF␣-induced signaling, their effect on receptor dimerization was measured. These studies demonstrated that quinazoline inhibitors per se induce inactive EGFR homodimers in EGFR-overexpressing cells or EGFR/ErbB-2 heterodimers in cells overexpressing ErbB-2 and containing lower levels of EGFR. The ability of the quinazolines to inhibit kinase function by sequestering receptors into inactive dimers appears related to their interaction with the receptor ATP binding site. These data suggest a novel biochemical mechanism of (inactive) receptor dimerization in which the initial monomer interactions are

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A point mutation at the ATP-binding site of the EGF-receptor abolishes signal transduction.

Cited by 207 publications

References 21 publications

Distinct cellular properties of oncogenic KIT receptor tyrosine kinase mutants enable alternative courses of cancer cell inhibition

Distinct cellular properties of oncogenic KIT receptor tyrosine kinase mutants enable alternative courses of cancer cell inhibition

Superagonistic activation of ErbB-1 by EGF-related growth factors with enhanced association and dissociation rate constants

Unliganded Epidermal Growth Factor Receptor Dimerization Induced by Direct Interaction of Quinazolines with the ATP Binding Site

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