W mutant mice with mild or severe developmental defects contain distinct point mutations in the kinase domain of the c-kit receptor.

Reith, Alastair D.; Rottapel, Robert; Giddens, Elizabeth B.; Brady, Catherine; Forrester, Lesley M.; Bernstein, Alan

doi:10.1101/gad.4.3.390

Cited by 325 publications

(203 citation statements)

References 63 publications

Supporting

Mentioning

195

Contrasting

Unclassified

Order By: Relevance

“…The Kit x/v mutation is a substituted amino acid in the Kit receptor kinase domain resulting in reduced kinase activity (Nocka et al, 1990;Reith et al, 1990). In Kit x/v mice, the surface epithelium of neonatal animals exhibited foci of crowded OSE cells up to several layers thick compared to non-mutant animals of the same strain (Murphy, 1972).…”

Section: Introductionmentioning

confidence: 99%

Transforming growth factor-β regulates Kit ligand expression in rat ovarian surface epithelial cells

1999

View full text Add to dashboard Cite

In preparation for ovulation, paracrine communication between the preovulatory follicle and overlying theca/ stromal cells and ovarian surface epithelium (OSE) must take place to facilitate the degradative and apoptotic events associated with ovulation. Kit tyrosine kinase receptors and their ligand, kit ligand (KL) are expressed within ovarian follicles, and ligand-induced receptor activation appears to account for some of the cell ± cell interactions important for oocyte development. We investigated the expression of Kit receptors and KL in OSE cells and the possibility that modulation of their expression could a ect OSE cell activity. KL mRNA and protein were detected in the OSE cell layer of rat ovaries, and primary cultures of rat OSE as well as the immortalized rat OSE cell line, ROSE 199, expressed KL, but not Kit receptors. Both primary and immortalized OSE cells preferentially expressed KL-1, rather than KL-2, transcripts, suggesting that these cells produce predominantly the soluble form of KL. Activation of the cAMP signalling pathway using dibutyryl cAMP decreased proliferation of ROSE 199 cells and elicited a threefold increase in KL expression. TGF-b similarly inhibited ROSE 199 cell proliferation, but strongly inhibited dibutyryl cAMP-induced KL expression, indicating that changes in KL expression were not directly associated with OSE cell proliferation. The expression of mostly soluble KL in the surface epithelium suggests that this cytokine may be acting in a paracrine fashion, perhaps interacting with nearby Kit receptorbearing theca cells.

show abstract

Section: Introductionmentioning

confidence: 99%

Transforming growth factor-β regulates Kit ligand expression in rat ovarian surface epithelial cells

1999

View full text Add to dashboard Cite

show abstract

“…W42 mutation is analogous to a spontaneously occuring loss of function point mutation identified in the W 42 dominant-negative allele of the c-kit receptor tyrosine kinase (Reith et al, 1990(Reith et al, , 1991) that serves as a dominant-negative mutation for other RTKs in cell culture models (Reith et al, 1993). EphA2-deficient cells were infected with LZRS retrovirus expressing wild-type EphA2 receptor (WT), W42 mutant, or vector control and kinase activity of each receptor variant was determined by in vitro kinase assay.…”

Section: Signaling-defective Forms Of Epha2 Mutants Inhibit 4t1 Mammamentioning

confidence: 99%

A kinase-dependent role for EphA2 receptor in promoting tumor growth and metastasis

et al. 2005

View full text Add to dashboard Cite

Receptor tyrosine kinases of the Eph family are upregulated in several different types of cancer. One family member in particular, the EphA2 receptor, has been linked to breast, prostate, lung and colon cancer, as well as melanoma. However, mechanisms by which EphA2 contributes to tumor progression are far from clear. In certain tumor cell lines, EphA2 receptor is underphosphorylated, raising the question of whether ligandinduced receptor phosphorylation and its kinase activity play a role in oncogenesis. To test directly the role of EphA2 receptor phosphorylation/kinase activity in tumor progression, we generated EphA2 receptor variants that were either lacking the cytoplasmic domain or carrying a point mutation that inhibits its kinase activity. Expression of these EphA2 mutants in breast cancer cells resulted in decreased tumor volume and increased tumor apoptosis in primary tumors. In addition, the numbers of lung metastases were significantly reduced in both experimental and spontaneous metastasis models. Reduced tumor volume and metastasis are not due to defects in tumor angiogenesis, as there is no significant difference in tumor vessel density between wild-type tumors and tumors expressing EphA2-signaling-defective mutants. In contrast, tumor cells expressing the EphA2 mutants are defective in RhoA GTPase activation and cell migration. Taken together, these results suggest that receptor phosphorylation and kinase activity of the EphA2 receptor, at least in part, contribute to tumor malignancy.

show abstract

“…10 For example, W v mutant mice with the C57BL/6 background have a point mutation in the cytoplasmic region of Kit, resulting in no coat pigmentation, severe anemia, a deficiency of mast cells and infertility in homozygotes (W v /W v ). 11,12 In reproductive organs, Kit plays essential roles in spermatogenesis and oogenesis. 10 In the testes, Kit receptor expression is restricted to differentiating type A to type B spermatogonia, primary spermatocytes and Leydig cells.…”

Section: Introductionmentioning

confidence: 99%

Involvement of death receptor Fas in germ cell degeneration in gonads of Kit-deficient Wv/Wv mutant mice

et al. 2003

View full text Add to dashboard Cite

Kit and its ligand stem cell factor (SCF) play a fundamental role in hematopoiesis, melanogenesis and gametogenesis. Homozygous W v mutant mice with a mutation in kit show abnormalities in these cell lineages. Fas is a member of the death receptor family inducing apoptosis. In this study, we generated double-mutant mice (W v /W v :Fas À/À ) and analyzed histologically their reproductive organs. In testes and ovaries of the double-mutant mice, testicular germ cells and oocytes were detected, respectively, whereas the same-aged W v /W v mice contained neither cells. In addition, inhibition of Kit signals by administration of anti-Kit mAb, which induces degeneration of testicular germ cells in vivo in wild-type mice, did not cause degeneration in Fas-deficient mice. In testicular germ cells of W v /W v mutant mice, an increase of Fas expression was observed in spermatogonia. Further, in vitro treatment with SCF was shown to downregulate Fas on fibroblasts expressing exogenous Kit through activation of PI3-kinase/Akt. All the results clearly indicate that Fasmediated apoptosis is involved in germ cell degeneration accompanied by defects in Kit-mediated signals, and Kit signaling negatively regulates Fas-mediated apoptosis in vivo.

show abstract

W mutant mice with mild or severe developmental defects contain distinct point mutations in the kinase domain of the c-kit receptor.

Cited by 325 publications

References 63 publications

Transforming growth factor-β regulates Kit ligand expression in rat ovarian surface epithelial cells

Transforming growth factor-β regulates Kit ligand expression in rat ovarian surface epithelial cells

A kinase-dependent role for EphA2 receptor in promoting tumor growth and metastasis

Involvement of death receptor Fas in germ cell degeneration in gonads of Kit-deficient Wv/Wv mutant mice

Contact Info

Product

Resources

About