Deficiency of Src family kinases compromises the repopulating ability of hematopoietic stem cells

Orschell, Christie M.; Borneo, Jovencio; Munugalavadla, Veerendra; Ma, Peilin; Sims, Emily; Ramdas, Baskar; Yoder, Mervin C.; Kapur, Reuben

doi:10.1016/j.exphem.2008.01.002

Cited by 13 publications

(11 citation statements)

References 46 publications

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“…However, SFK activity is not required for adhesion structure assembly or function and, in contrast to adherent cells, its impact on the stability of the attachment is limited. With regard to documented involvement of Lyn in many important processes in immature haematopoietic cells, 10,44 we suppose that the role of Lyn in adhesion structures of these cells is to link the cell-matrix interaction to signaling regulating cell growth and survival.…”

Section: Discussionmentioning

confidence: 99%

“…Lyn depletion leads to decreased migration rate in neutrophiles 9 and macrophages. 8 Lyn is also required for long-term engraftment of trasplanted haematopoietic stem and progenitor cells 10 as well as for platelet activation and thrombus formation. 11 Several papers suggested a role for Lyn in migration and adhesion of adherent cells, too.…”

Section: Introductionmentioning

confidence: 99%

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Adhesion structures in leukemia cells and their regulation by Src family kinases

Röselová

Obr

Holoubek

et al. 2017

Cell Adhesion & Migration

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Interaction of leukemia blasts with the bone marrow extracellular matrix often results in protection of leukemia cells from chemotherapy and in persistence of the residual disease which is on the basis of subsequent relapses. The adhesion signaling pathways have been extensively studied in adherent cells as well as in mature haematopoietic cells, but the adhesion structures and signaling in haematopoietic stem and progenitor cells, either normal or malignant, are much less explored. We analyzed the interaction of leukemia cells with fibronectin (FN) using interference reflection microscopy, immunofluorescence, measurement of adherent cell fraction, real-time microimpedance measurement and live cell imaging. We found that leukemia cells form very dynamic adhesion structures similar to early stages of focal adhesions. In contrast to adherent cells, where Src family kinases (SFK) belong to important regulators of focal adhesion dynamics, we observed only minor effects of SFK inhibitor dasatinib on leukemia cell binding to FN. The relatively weak involvement of SFK in adhesion structure regulation might be associated with the lack of cytoskeletal mechanical tension in leukemia cells. On the other hand, active Lyn kinase was found to specifically localize to leukemia cell adhesion structures and a less firm cell attachment to FN was often associated with higher Lyn activity (this unexpectedly occurred also after cell treatment with the inhibitor SKI-1). Lyn thus may be important for signaling from integrin-associated complexes to other processes in leukemia cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Adhesion structures in leukemia cells and their regulation by Src family kinases

Röselová

Obr

Holoubek

et al. 2017

Cell Adhesion & Migration

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show abstract

“…Src kinases were shown to regulate ␤ 1 and ␤ 2 integrins in diff erent cells and cell lines ( 28,36 ). Moreover, in mice defi cient in members of the Src family, immature, hematopoietic Sca-1 + cells demonstrated increased homing ( 37 ), and primitive, BM-derived SKL cells showed enhanced G-CSF -induced mobilization that was associated with elevated MMP-9 and accelerated breakdown of vascular cell adhesion molecule 1 ( 38 ). In line with these studies, our results demonstrate the opposite eff ects when Src is hyperactive because of CD45 defi ciency.…”

Section: Discussionmentioning

confidence: 99%

CD45 regulates retention, motility, and numbers of hematopoietic progenitors, and affects osteoclast remodeling of metaphyseal trabecules

Lapid¹,

Schajnovitz²,

Goichberg³

et al. 2008

The Journal of Experimental Medicine

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The CD45 phosphatase is uniquely expressed by all leukocytes, but its role in regulating hematopoietic progenitors is poorly understood. We show that enhanced CD45 expression on bone marrow (BM) leukocytes correlates with increased cell motility in response to stress signals. Moreover, immature CD45 knockout (KO) cells showed defective motility, including reduced homing (both steady state and in response to stromal-derived factor 1) and reduced granulocyte colony-stimulating factor mobilization. These defects were associated with increased cell adhesion mediated by reduced matrix metalloproteinase 9 secretion and imbalanced Src kinase activity. Poor mobilization of CD45KO progenitors by the receptor activator of nuclear factor B ligand, and impaired modulation of the endosteal components osteopontin and stem cell factor, suggested defective osteoclast function. Indeed, CD45KO osteoclasts exhibited impaired bone remodeling and abnormal morphology, which we attributed to defective cell fusion and Src function. This led to irregular distribution of metaphyseal bone trabecules, a region enriched with stem cell niches. Consequently, CD45KO mice had less primitive cells in the BM and increased numbers of these cells in the spleen, yet with reduced homing and repopulation potential. Uncoupling environmental and intrinsic defects in chimeric mice, we demonstrated that CD45 regulates progenitor movement and retention by infl uencing both the hematopoietic and nonhematopoietic compartments.

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“…104,105 The active interaction of SFKs with FAK is essential for the integrin-mediated regulation of Rho GTPases. 106 The small…”

Section: Integrin-mediated Signallingmentioning

confidence: 99%

Biophysical regulation of hematopoietic stem cells

Lee-Thedieck

Spatz

2014

Biomater. Sci.

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Deficiency of Src family kinases compromises the repopulating ability of hematopoietic stem cells

Cited by 13 publications

References 46 publications

Adhesion structures in leukemia cells and their regulation by Src family kinases

Adhesion structures in leukemia cells and their regulation by Src family kinases

CD45 regulates retention, motility, and numbers of hematopoietic progenitors, and affects osteoclast remodeling of metaphyseal trabecules

Biophysical regulation of hematopoietic stem cells

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