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PMID:23528453

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Citation

Gustafsson, K, Heffner, G, Wenzel, PL, Curran, M, Grawé, J, McKinney-Freeman, SL, Daley, GQ and Welsh, M (2013) The Src homology 2 protein Shb promotes cell cycle progression in murine hematopoietic stem cells by regulation of focal adhesion kinase activity. Exp. Cell Res. 319:1852-64

Abstract

The widely expressed adaptor protein Shb has previously been reported to contribute to T cell function due to its association with the T cell receptor and furthermore, several of Shb's known interaction partners are established regulators of blood cell development and function. In addition, Shb deficient embryonic stem cells displayed reduced blood cell colony formation upon differentiation in vitro. The aim of the current study was therefore to explore hematopoietic stem and progenitor cell function in the Shb knockout mouse. Shb deficient bone marrow contained reduced relative numbers of long-term hematopoietic stem cells (LT-HSCs) that exhibited lower proliferation rates. Despite this, Shb knockout LT-HSCs responded promptly by entering the cell cycle in response to genotoxic stress by 5-fluorouracil treatment. In competitive LT-HSC transplantations, Shb null cells initially engrafted as well as the wild-type cells but provided less myeloid expansion over time. Moreover, Shb knockout bone marrow cells exhibited elevated basal activities of focal adhesion kinase/Rac1/p21-activated kinase signaling and reduced responsiveness to Stem Cell Factor stimulation. Consequently, treatment with a focal adhesion kinase inhibitor increased Shb knockout LT-HSC proliferation. The altered signaling characteristics thus provide a plausible mechanistic explanation for the changes in LT-HSC proliferation since these signaling intermediates have all been shown to participate in LT-HSC cell cycle control. In summary, the loss of Shb dependent signaling in bone marrow cells, resulting in elevated focal adhesion kinase activity and reduced proliferative responses in LT-HSCs under steady state hematopoiesis, confers a disadvantage to the maintenance of LT-HSCs over time.

Links

PubMed Online version:10.1016/j.yexcr.2013.03.020

Keywords

Animals; Cell Cycle; Cell Proliferation; DNA Damage; Fluorouracil/toxicity; Focal Adhesion Protein-Tyrosine Kinases/metabolism; Hematopoietic Stem Cells/cytology; Hematopoietic Stem Cells/metabolism; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Neuropeptides/metabolism; Proto-Oncogene Proteins/genetics; Proto-Oncogene Proteins/metabolism; Signal Transduction; Stem Cell Factor/metabolism; p21-Activated Kinases/metabolism; rac GTP-Binding Proteins/metabolism; rac1 GTP-Binding Protein

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:PAK1

enables

GO:0004672: protein kinase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:FLT3

located_in

GO:0009897: external side of plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000034)

Seeded From UniProt

complete

MOUSE:SLAF1

located_in

GO:0009897: external side of plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:SHB

acts_upstream_of_or_within

GO:0006469: negative regulation of protein kinase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3721903

P

Seeded From UniProt

complete

MOUSE:SHB

acts_upstream_of_or_within

GO:0045931: positive regulation of mitotic cell cycle

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3721903

P

Seeded From UniProt

complete

MOUSE:SHB

acts_upstream_of_or_within

GO:0071425: hematopoietic stem cell proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3721903

P

Seeded From UniProt

complete

MOUSE:RAC1

enables

GO:0005525: GTP binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

Notes

See also

References

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