The Src homology 2 protein Shb promotes cell cycle progression in murine hematopoietic stem cells by regulation of focal adhesion kinase activity

Gustafsson, Karin; Heffner, Garrett C.; Wenzel, Pamela L.; Curran, Matthew; Grawé, Jan; McKinney‐Freeman, Shannon; Daley, George Q.; Welsh, Michael

doi:10.1016/j.yexcr.2013.03.020

Cited by 13 publications

(27 citation statements)

References 49 publications

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“…Basal FAK activity at 5.6 mM glucose was elevated as a consequence of absence of Shb. The increase was modest (42%) but typical for the level of increase previously observed as a consequence of Shb deficiency , Gustafsson et al 2013. Downstream of FAK in b-cells are IRS-proteins (Baron et al 1998).…”

Section: Characteristics Of Tyrosine Kinase Signal Transduction In Shsupporting

confidence: 59%

Absence of Shb impairs insulin secretion by elevated FAK activity in pancreatic islets

Alenkvist¹,

Dyachok²,

Tian³

et al. 2014

Journal of Endocrinology

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The Src homology-2 domain containing protein B (SHB) has previously been shown to function as a pleiotropic adapter protein, conveying signals from receptor tyrosine kinases to intracellular signaling intermediates. The overexpression of Shb in b-cells promotes b-cell proliferation by increased insulin receptor substrate (IRS) and focal adhesion kinase (FAK) activity, whereas Shb deficiency causes moderate glucose intolerance and impaired first-peak insulin secretion. Using an array of techniques, including live-cell imaging, patch-clamping, immunoblotting, and semi-quantitative PCR, we presently investigated the causes of the abnormal insulin secretory characteristics in Shb-knockout mice. Shb-knockout islets displayed an abnormal signaling signature with increased activities of FAK, IRS, and AKT. b-catenin protein expression was elevated and it showed increased nuclear localization. However, there were no major alterations in the gene expression of various proteins involved in the b-cell secretory machinery. Nor was Shb deficiency associated with changes in glucose-induced ATP generation or cytoplasmic Ca 2C handling. In contrast, the glucose-induced rise in cAMP, known to be important for the insulin secretory response, was delayed in the Shb-knockout compared with WT control. Inhibition of FAK increased the submembrane cAMP concentration, implicating FAK activity in the regulation of insulin exocytosis. In conclusion, Shb deficiency causes a chronic increase in b-cell FAK activity that perturbs the normal insulin secretory characteristics of b-cells, suggesting multi-faceted effects of FAK on insulin secretion depending on the mechanism of FAK activation.

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Section: Characteristics Of Tyrosine Kinase Signal Transduction In Shsupporting

confidence: 59%

Absence of Shb impairs insulin secretion by elevated FAK activity in pancreatic islets

Alenkvist¹,

Dyachok²,

Tian³

et al. 2014

Journal of Endocrinology

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“…FAK activity is under complex control involving numerous elements and/or processes (Tomakidi et al 2014, Lee et al 2015. The SHB/FAK relationship is described above and this interaction will have implications for several downstream signaling systems, such as the Akt, ERK and Rac1 pathways as observed in b cells, endothelial cells and hematopoietic stem cells , Gustafsson et al 2013, Alenkvist et al 2014. Curiously, both SHB overexpression and absence of SHB seem to have similar effects on FAK activity, with increased basal activity and reduced ligand responsiveness.…”

Section: Shb and The Fakmentioning

confidence: 94%

“…The Shb knockout mouse also displays hematopoietic abnormalities (Gustafsson et al 2013(Gustafsson et al , 2014a. These include reduced peripheral blood lymphocytes and monocytes and a Th2 skewing of the T cell receptor response upon activation due to elevated basal T cell receptor signaling in the absence of Shb (Gustafsson et al 2011).…”

Section: Hematopoietic Abnormalitiesmentioning

confidence: 99%

“…The consequence of these aberrations was an increased propensity for atopic dermatitis upon stimulation with an allergy-inducing agent (Gustafsson et al 2014b). The bone marrow of Shb knockout mice displayed a reduced cell number and proliferation of hematopoietic stem cells (HSC) (Gustafsson et al 2013). When such Shb knockout cells were subject to competitive transplantation experiments, they initially performed well in repopulating bone-marrow-depleted recipients but eventually lagged in efficacy, causing relatively less contribution to the myeloid lineages than wild type (WT) cells at 16 weeks after transplantation.…”

Section: Hematopoietic Abnormalitiesmentioning

confidence: 99%

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The role of the Src Homology-2 domain containing protein B (SHB) in β cells

Welsh

Jamalpour

Zang

et al. 2015

Journal of Molecular Endocrinology

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This review will describe the SH2-domain signaling protein Src Homology-2 domain containing protein B (SHB) and its role in various physiological processes relating in particular to glucose homeostasis and b cell function. SHB operates downstream of several tyrosine kinase receptors and assembles signaling complexes in response to receptor activation by interacting with other signaling proteins via its other domains (proline-rich, phosphotyrosine-binding and tyrosine-phosphorylation sites). The subsequent responses are context-dependent. Absence of Shb in mice has been found to exert effects on hematopoiesis, angiogenesis and glucose metabolism. Specifically, first-phase insulin secretion in response to glucose was impaired and this effect was related to altered characteristics of focal adhesion kinase activation modulating signaling through Akt, ERK, b catenin and cAMP. It is believed that SHB plays a role in integrating adaptive responses to various stimuli by simultaneously modulating cellular responses in different cell-types, thus playing a role in maintaining physiological homeostasis.

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“…depositions. ECM will regulate focal adhesion kinase (FAK), which suppresses LT-HSC proliferation (15,27). On the other hand, in BCR-…”

Section: Commentarymentioning

confidence: 99%

Maintenance of hematopoietic stem cell dormancy: yet another role for the macrophage

Gustafsson

Welsh

2016

Stem Cell Investig.

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The Src homology 2 protein Shb promotes cell cycle progression in murine hematopoietic stem cells by regulation of focal adhesion kinase activity

Cited by 13 publications

References 49 publications

Absence of Shb impairs insulin secretion by elevated FAK activity in pancreatic islets

Absence of Shb impairs insulin secretion by elevated FAK activity in pancreatic islets

The role of the Src Homology-2 domain containing protein B (SHB) in β cells

Maintenance of hematopoietic stem cell dormancy: yet another role for the macrophage

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