Kinase-Dependent and Kinase-Independent Functions of EphA4 Receptors in Major Axon Tract Formation In Vivo

Kullander, Klas; Mather, Nicole K.; Diella, Francesca; Dottori, Mirella; Boyd, Andrew W.; Klein, Rüdiger

doi:10.1016/s0896-6273(01)00181-7

Cited by 237 publications

(212 citation statements)

References 52 publications

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“…All mutant Kit receptors were autophosphorylated in response to SCF in 293 cells (Fig. 5A), indicating that substitution of the Jx tyrosines does not lead to a complete failure of kinase activation, as observed for Eph receptors (20,21,30). However, tyrosine phosphorylation of the 567F and 569F single mutant receptors was reduced compared with wild-type and phosphorylation of the FF double mutant receptor was even further decreased.…”

Section: The Jx Tyrosine Mutations Cause Differences In Downstream Simentioning

confidence: 70%

“…These mutations might therefore uncouple a specific pathway(s) activated by tyrosine phosphorylation of residues 567 and 569 from the other pathways regulated by the Kit RTK. In contrast to Eph receptors, such as EphA4, for which substitution of the Jx tyrosines with phenylalanine results in constitutive autoinhibition of the kinase domain and a kinase inactive phenotype in vivo (30), the Kit FF mutant receptor retains partial signaling activity. These data suggest that the precise molecular mechanisms by which the Kit and Eph receptor Jx regions regulate kinase activity are likely to be distinct.…”

Section: Discussionmentioning

confidence: 90%

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Targeted mutations of the juxtamembrane tyrosines in the Kit receptor tyrosine kinase selectively affect multiple cell lineages

Kimura

Jones

Klüppel

et al. 2004

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

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Loss-of-function mutations in the murine dominant white spotting ͞c-kit locus affect a diverse array of biological processes and cell lineages and cause a range of phenotypes, including severe anemia, defective pigmentation, sterility, mast cell deficits, a lack of interstitial cells of Cajal, spatial learning memory deficits, and defects in peripheral nerve regeneration. Here we show that tyrosine residues 567 and 569 in the juxtamembrane (Jx) domain of the murine Kit receptor tyrosine kinase are crucial for the function of Kit in melanogenesis and mast cell development, but are dispensable for the normal development of erythroid, interstitial cells of Cajal and germ cells. Furthermore, adult mice lacking both tyrosines exhibit splenomegaly, dysregulation of B-cell and megakaryocyte development, and enlarged stomachs. Analysis of signal transduction events induced by the mutant receptors after ligand stimulation indicates that Jx tyrosine mutations diminish receptor autophosphorylation and selectively attenuate activation of extracellular signal-regulated kinase͞mitogen-activated protein kinases. Together, these observations demonstrate that the Jx domain of Kit plays a cell-type specific regulatory role in vivo and illustrate how engineered mutations in Kit can be used to understand the complex biological and molecular events that result from activating a receptor tyrosine kinase.T he Kit receptor tyrosine kinase (RTK) is centrally involved in the development of multiple cell lineages, including hematopoietic and germ cells, melanocytes, and the interstitial cells of Cajal (ICC) (1-4). Insights into the roles of this receptor and its cognate ligand, stem cell factor (SCF), in these developmental processes have been greatly facilitated by the large series of naturally occurring mutations in the murine genes that encode these molecules, the dominant white spotting (W) and steel (Sl) loci, respectively. Thus, mice with loss-of-functions in either the W or Sl loci are anemic and exhibit white spotting, sterility, and a concomitant loss of the ICC and intestinal pacemaker activity.Ligand binding to the Kit RTK induces receptor dimerization and autophosphorylation of specific tyrosine residues (5, 6). These phosphorylation events create docking sites for specific Src homology 2 (SH2) domain-containing proteins, which in turn control various intracellular signaling pathways (7). Recruitment of particular targets is mediated by the ability of their SH2 domains to recognize specific phosphotyrosine (pTyr)-containing motifs on the activated receptor (8). Numerous signaling molecules have been identified as binding partners for specific pTyr residues on activated Kit, including the p85 subunit of phosphatidylinositol 3Ј kinase (by means of tyrosine 719), phospholipase C␥ (by means of tyrosine 728), and the Grb2 and Grb7 adapter proteins (by means of tyrosine residues 702 and 934) (6). Additionally, signaling molecules, including Src family kinases and the protein tyrosine phosphatases Shp-1 and Shp-2, have been shown to ...

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Section: The Jx Tyrosine Mutations Cause Differences In Downstream Simentioning

confidence: 70%

Section: Discussionmentioning

confidence: 90%

Targeted mutations of the juxtamembrane tyrosines in the Kit receptor tyrosine kinase selectively affect multiple cell lineages

Kimura

Jones

Klüppel

et al. 2004

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

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“…Genetic studies in vivo have shown that Eph receptors have both kinase-dependent and -independent functions (Birgbauer et al, 2000;Dalva et al, 2000;Grunwald et al, 2001;Kullander et al, 2001). In addition, some Eph receptors either have kinase-deficient variant forms generated by alternative splicing (EphA6, 7, and B1) (Zisch and Pasquale, 1997) or have kinase domains with defective catalytic activity (EphB6 and A10) (Gurniak and Berg, 1996;Manning et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2005

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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.

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“…Knock out studies in the mouse support the idea that signals mediated by ephrin-B1 and ephrin-B3 control axon pathfinding in the embryonic brain anterior commissure and the developing retina (13,14), whereas signals mediated by ephrin-B2 control the formation of the vascular system (15,16).…”

mentioning

confidence: 91%

In Vivo Tyrosine Phosphorylation Sites of Activated Ephrin-B1 and EphB2 from Neural Tissue

Kalo

Pasquale

2001

Journal of Biological Chemistry

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EphB2 is a receptor tyrosine kinase of the Eph family and ephrin-B1 is one of its transmembrane ligands. In the embryo, EphB2 and ephrin-B1 participate in neuronal axon guidance, neural crest cell migration, the formation of blood vessels, and the development of facial structures and the inner ear. Interestingly, EphB2 and ephrin-B1 can both signal through their cytoplasmic domains and become tyrosine-phosphorylated when bound to each other. Tyrosine phosphorylation regulates EphB2 signaling and likely also ephrin-B1 signaling. Embryonic retina is a tissue that highly expresses both ephrin-B1 and EphB2. Although the expression patterns of EphB2 and ephrin-B1 in the retina are different, they partially overlap, and both proteins are substantially tyrosine-phosphorylated. To understand the role of ephrin-B1 phosphorylation, we have identified three tyrosines of ephrin-B1 as in vivo phosphorylation sites in transfected 293 cells stimulated with soluble EphB2 by using mass spectrometry and site-directed mutagenesis. These tyrosines are also physiologically phosphorylated in the embryonic retina, although the extent of phosphorylation at each site may differ.

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Kinase-Dependent and Kinase-Independent Functions of EphA4 Receptors in Major Axon Tract Formation In Vivo

Cited by 237 publications

References 52 publications

Targeted mutations of the juxtamembrane tyrosines in the Kit receptor tyrosine kinase selectively affect multiple cell lineages

Targeted mutations of the juxtamembrane tyrosines in the Kit receptor tyrosine kinase selectively affect multiple cell lineages

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

In Vivo Tyrosine Phosphorylation Sites of Activated Ephrin-B1 and EphB2 from Neural Tissue

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