These CskAS mice express a conditionally inhibitory CSK protein and lack endogenous CSK expression. They may be useful for studying the requirements of Csk on the control of TCR signaling.
Dr. Arthur Weiss, University of California, San Francisco
|Allele Type||Gene Symbol||Gene Name|
|Targeted||Csk||c-src tyrosine kinase|
|Transgenic (Inserted expressed sequence)|
Mice hemizygous for the BAC CskAS transgene are viable and fertile. These mice do not express the endogenous c-src tyrosine kinase (CSK) protein. These mice do express mutant CSK, from the BAC transgene, which contains a point mutation at position 266 resulting in a threonine to glycine mutation. This mutation creates a larger ATP-binding pocket in the expressed protein, allowing for specific and rapid inhibition by an analog of the kinase inhibitor PP1, 3-iodo-benzyl-PP1 (3-IB-PP1). CSK is a cytosolic tyrosine-protein kinase that plays a role in the regulation of cell growth, differentiation, migration and immune response. CSK phosphorylates tyrosine residues located in the C-terminal tails of Src-family kinases (SFKs), which in turn suppress signaling by surface receptors including T-cell receptor (TCR) and B-cell receptor (BCR). CskAS mice have 2.5-fold as much expression of CSK as wild-type mice and display normal T cell development. Inhibition of CSK with 3-IB-PP1 in thymocytes induces activation of SFKs and proximal TCR signaling. Defects in inositol phosphates, intracellular calcium, and phosphorylation of Erk are also seen, although remodeling of the actin cytoskeleton is sufficient to reverse these defects and to allow full TCR signaling. Mice hemizygous for the CSK* transgene and homozygous for Csktm1Sor allele are viable and fertile. The Csktm1Sor allele alone is homozygous embryonic lethal. The donating investigator has not tried to make CSK* transgenic homozygous mice.
Bacterial artificial chromosome (BAC) library (CHORI) was used to obtain a BAC (#RP24-400B5) containing the entire mouse Csk (c-src tyrosine kinase) gene. A point mutation was introduced in Csk at position 266 resulting in a threonine to glycine mutation, inducing a larger ATP-binding pocket to be formed in the expressed protein. To inactivate other genes present in the BAC, both ends of the BAC were deleted, leaving 74kb of sequence, and an in-frame stop codon was inserted in exon 2 of Lman1l (lectin, mannose-binding 1 like) gene. This BAC was microinjected into fertilized C57BL/6 oocytes. CskAS mice from founder line 2 were maintained by breeding transgenic mice with mice carrying the Csktm1Sor/J allele that have been bred to C57BL/6 mice for at least 13 generations (similar to Stock No. 003201). These mice were maintained on a C57BL/6 background. Upon arrival at The Jackson Laboratory, mice were bred to C57BL/6J inbred mice (Stock No. 000664) for at least one generation to establish the colony.
|Expressed Gene||Csk, c-src tyrosine kinase, mouse, laboratory|
|Site of Expression|
|Allele Name||targeted mutation 1, Philippe Soriano|
|Allele Type||Targeted (Null/Knockout)|
|Gene Symbol and Name||Csk, c-src tyrosine kinase|
|Gene Synonym(s)||AW212630; expressed sequence AW212630|
|Strain of Origin||129S7/SvEvBrd-Hprt<+>|
|Molecular Note||Deletion of all coding sequences and replacement with a neomycin cassette.|
|Mutations Made By|| |
Dr. Philippe Soriano, Mount Sinai School of Medicine
|Allele Name||transgene insertion 2, Arthur Weiss|
|Allele Type||Transgenic (Inserted expressed sequence)|
|Gene Symbol and Name||Tg(Csk*)2Weis, transgene insertion 2, Arthur Weiss|
|Promoter||Csk, c-src tyrosine kinase, mouse, laboratory|
|Expressed Gene||Csk, c-src tyrosine kinase, mouse, laboratory|
|Strain of Origin||C57BL/6|
|Molecular Note||A bacterial artificial chromosome (BAC) library from CHORI was used to obtain a BAC (#RP24-400B5) containing the entire mouse Csk (c-src tyrosine kinase) gene. A point mutation was introduced in Csk at position 266 resulting in a threonine to glycine mutation, inducing a larger ATP-binding pocket to be formed in the expressed protein. To inactivate other genes present in the BAC, both ends of the BAC were deleted, leaving 74kb of sequence, and an in-frame stop codon was inserted in exon 2 of Lman1l (lectin, mannose-binding 1 like) gene.|
When maintaining a live colony, mice hemizygous for the CSK* transgene and homozygous for Csktm1Sor may be bred to mice heterozygous for Csktm1Sor, or to wildtype mice from the colony, or to C57BL/6J (Stock No. 000664). The Csk
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