Integrin β1 Signals through Arg to Regulate Postnatal Dendritic Arborization, Synapse Density, and Behavior

Warren, Michael S.; Bradley, William D.; Gourley, Shannon L.; Lin, Yu‐Chih; Simpson, Mark A.; Reichardt, Louis F.; Greer, Charles A.; Taylor, Jane R.; Koleske, Anthony J.

doi:10.1523/jneurosci.3942-11.2012

Cited by 100 publications

(142 citation statements)

References 58 publications

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“…These examples illustrate that regulation of Rac1 and Rap1 by Abl kinases is cell-context-and stimulus-dependent. In response to integrin engagement, ABL2 inhibits RhoA in fibroblasts and dendritic spines by phosphorylating p190RhoGAP (also known as ARHGAP35) that, in turn, inhibits RhoA (Bradley and Koleske, 2009;Warren et al, 2012). However, activation of Abl kinase downstream of the ligand-stimulated RTK MET promotes activation of RhoA (Li et al, 2015).…”

Section: Structure Modular Domains and Enzymatic Regulation Of The Amentioning

confidence: 99%

Multifunctional Abl kinases in health and disease

Khatri

Wang

Pendergast

2016

Journal of Cell Science

117

145

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The Abelson tyrosine kinases were initially identified as drivers of leukemia in mice and humans. The Abl family kinases Abl1 and Abl2 regulate diverse cellular processes during development and normal homeostasis, and their functions are subverted during inflammation, cancer and other pathologies. Abl kinases can be activated by multiple stimuli leading to cytoskeletal reorganization required for cell morphogenesis, motility, adhesion and polarity. Depending on the cellular context, Abl kinases regulate cell survival and proliferation. Emerging data support important roles for Abl kinases in pathologies linked to inflammation. Among these are neurodegenerative diseases and inflammatory pathologies. Unexpectedly, Abl kinases have also been identified as important players in mammalian host cells during microbial pathogenesis. Thus, the use of Abl kinase inhibitors might prove to be effective in the treatment of pathologies beyond leukemia and solid tumors. In this Cell Science at a Glance article and in the accompanying poster, we highlight the emerging roles of Abl kinases in the regulation of cellular processes in normal cells and diverse pathologies ranging from cancer to microbial pathogenesis.

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Section: Structure Modular Domains and Enzymatic Regulation Of The Amentioning

confidence: 99%

Multifunctional Abl kinases in health and disease

Khatri

Wang

Pendergast

2016

Journal of Cell Science

117

145

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“…Cyr61 is a ligand of ␤1-integrin (CD29) in fibroblasts (46,47). ␤1-Integrin is also crucial for proper dendritic arbor morphology (48,49). If Cyr61 acts via ␤1-integrin, then the effects of Cyr61-GFP overexpression should be diminished by a ␤1-integrin-blocking antibody.…”

Section: Cyr61 Is Sufficient To Induce Dendritic Growth Of Both Develmentioning

confidence: 99%

Cyr61, a Matricellular Protein, Is Needed for Dendritic Arborization of Hippocampal Neurons

Malik¹,

Urbańska²,

Gozdz³

et al. 2013

Journal of Biological Chemistry

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“…Integrin engagement stimulates Abl family kinases to interact with and phosphorylate activators of the actinpolymerizing Arp2/3 complex in fibroblasts (5,27,28,29,34,36,61), causing dynamic cell edge protrusions resembling phagocytic intermediates. Interestingly, Abl family kinases have been implicated in endocytosis (21,58,59), macropinocytosis (13), and autophagy (66).…”

mentioning

confidence: 99%

“…To measure relative Abl or Arg activation after receptor engagement, phorbol-12-myristate-13-acetate (PMA; Sigma)-activated, macrophage colony-stimulating factor (M-CSF)-starved WT, abl Ϫ/Ϫ , arg Ϫ/Ϫ , or dKO Ms were added to dishes that were coated with C3bi or rabbit IgG1 (Sigma) for 15 min and lysed with a buffer of 20 mM Tris, 150 mM NaCl, 2 mM EDTA, and 1% Triton X-100 that contained protease and phosphatase inhibitors (61). Lysates of WT Ms allowed to spread on uncoated dishes were run to confirm that Crk was phosphorylated in response to CR3 or FcR engagement.…”

mentioning

confidence: 99%

The Abl and Arg Kinases Mediate Distinct Modes of Phagocytosis and Are Required for Maximal Leishmania Infection

Wetzel

McMahon-Pratt

Koleske

2012

Molecular and Cellular Biology

130

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Leishmania, an obligate intracellular parasite, binds several receptors to trigger engulfment by phagocytes, leading to cutaneous or visceral disease. These receptors include complement receptor 3 (CR3), used by promastigotes, and the Fc receptor (FcR), used by amastigotes. The mechanisms mediating uptake are not well understood. Here we show that Abl family kinases mediate both phagocytosis and the uptake of Leishmania amazonensis by macrophages (Ms). Imatinib, an Abl/Arg kinase inhibitor, decreases opsonized polystyrene bead phagocytosis and Leishmania uptake. Interestingly, phagocytosis of IgG-coated beads is decreased in Arg-deficient Ms, while that of C3bi-coated beads is unaffected. Conversely, uptake of C3bi-coated beads is decreased in Abl-deficient Ms, but that of IgG-coated beads is unaffected. Consistent with these results, Abl-deficient Ms are inefficient at C3bi-opsonized promastigote uptake, and Arg-deficient Ms are defective in IgG1-opsonized amastigote uptake. Finally, genetic loss of Abl or Arg reduces infection severity in murine cutaneous leishmaniasis, and imatinib treatment results in smaller lesions with fewer parasites than in controls. Our studies are the first to demonstrate that efficient phagocytosis and maximal Leishmania infection require Abl family kinases. These results highlight Abl family kinase-mediated signaling pathways as potential therapeutic targets for leishmaniasis. L eishmania parasites cause cutaneous or visceral disease in 1 to 2 million people a year in the developing world (17). Leishmania undergoes two life cycle stages: (i) the promastigote, found in the sand fly, and (ii) the amastigote, found in mammalian hosts. When an infected sand fly bites a host, the injected promastigotes must be engulfed by phagocytes to establish infection. The promastigotes then differentiate into amastigotes within the phagolysosome. If the amastigote finds itself outside a cell, it must be reengulfed for continued infection (23).Several M surface proteins permit Leishmania uptake. Promastigote internalization is mediated by the fibronectin receptor (integrin ␣5␤1) (2), the mannose-fucose receptor (63, 64), and complement receptors CR1 (10) and CR3 (38). Promastigotes may interact directly with CR3 (49), but binding is facilitated by opsonization with C3bi, a complement component (22,37,40,45). Both CR3 and the Fc receptor (FcR) mediate amastigote uptake (16); interactions with the latter are facilitated by IgG opsonization (35). The FcR subclass Fc␥R, which mediates IgG-mediated phagocytosis (33), is most likely responsible for amastigote uptake by Ms. Indeed, internalization of IgG-opsonized amastigotes via FcR␥I and -III sustains infection in murine cutaneous leishmaniasis (8,24,65). Adhesion of Leishmania to any of these receptors causes an actin-rich phagocytic cup to form and engulf the parasite (30). Our study explores the requirement for actin regulatory proteins in efficient Leishmania internalization.The Abl family kinases Abl and Arg translate signals from adhesion and growth...

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Integrin β1 Signals through Arg to Regulate Postnatal Dendritic Arborization, Synapse Density, and Behavior

Cited by 100 publications

References 58 publications

Multifunctional Abl kinases in health and disease

Multifunctional Abl kinases in health and disease

Cyr61, a Matricellular Protein, Is Needed for Dendritic Arborization of Hippocampal Neurons

The Abl and Arg Kinases Mediate Distinct Modes of Phagocytosis and Are Required for Maximal Leishmania Infection

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