Professor, Depts. of Medicine and Biochemistry, Microbiology & Immunology
University of Ottawa
Career Scientist, Ottawa Regional Cancer Centre
Associate Scientist, The Ottawa Hospital Research Institute
Telephone: 613-737-7700 ext 6893
Fax: 613-247-3524
Email: [email protected]
The control of pre-mRNA splicing by the Clk kinase family
We are studying a family of kinases which we believe provide an interface between intracellular signaling networks and the post-transcriptional mechanism of mRNA splicing. We are performing a structure:function analysis of the three Clk family members to identify domains in the three proteins which are involved in regulating splicing. Using homologous recombination we are generating null strains of mice which are lacking one, two or all three Clk genes. The Clk kinases all possess dual specificity kinase activity and yeast expression systems are being used to produce large amounts of the kinase to perform a detailed analysis of the sites of serine, threonine and tyrosine autophosphorylation within the kinase.
CLK2
GeneProduct
CLK3
GeneProduct
CLK4
GeneProduct
CPSF1
GeneProduct
CSTF2
GeneProduct
CSTF2T
GeneProduct
DDX1
GeneProduct
DDX20
GeneProduct
DHX15
GeneProduct
DHX38
GeneProduct
DHX8
GeneProduct
DHX9
GeneProduct
DICER1
GeneProduct
DNAJC8
GeneProduct
EFTUD2
GeneProduct
FNBP3
GeneProduct
FUSIP1
GeneProduct
FUSI_MOUSE PMID: 11684676
HEAB
GeneProduct
HNRPA2B1
GeneProduct
HNRPA3
GeneProduct
HNRPC
GeneProduct
HNRPD
GeneProduct
HNRPH2
GeneProduct
HNRPM
GeneProduct
HNRPR
GeneProduct
HRMT1L1
GeneProduct
LSM7
GeneProduct
NCBP1
GeneProduct
NXF1
GeneProduct
POLR2A
GeneProduct
PRPF3
GeneProduct
PRPF8
GeneProduct
PSKH1
GeneProduct
PMID: 12466556
PTBP2
GeneProduct
RBM5
GeneProduct
RBMX
GeneProduct
RNMT
GeneProduct
RNPS1
GeneProduct
PMID: 14729963
RNU2
GeneProduct
GenBank sequence: K00027
Rnu6
GeneProduct
GenBank sequence: M10329
SF3A3
GeneProduct
SF3B1
GeneProduct
SF3B2
GeneProduct
SF4
GeneProduct
inferred from: SURP 2, G patch protein, UniProt:O60378
PMID: 14559993. SRrp86 is a unique member of the SR protein superfamily containing one RNA recognition motif and two serine-arginine (SR)-rich domains separated by an unusual glutamic acid-lysine (EK)-rich region. Previously, we showed that SRrp86 could regulate alternative splicing by both positively and negatively modulating the activity of other SR proteins and that the unique EK domain could inhibit both constitutive and alternative splicing. These functions were most consistent with the model in which SRrp86 functions by interacting with and thereby modulating the activity of target proteins. To identify the specific proteins that interact with SRrp86, we used a yeast two-hybrid library screen and immunoprecipitation coupled to mass spectrometry. We show that SRrp86 interacts with all of the core SR proteins, as well as a subset of other splicing regulatory proteins, including SAF-B, hnRNP G, YB-1, and p72. In contrast to previous results that showed activation of SRp20 by SRrp86, we now show that SAF-B, hnRNP G, and 9G8 all antagonize the activity of SRrp86. Overall, we conclude that not only does SRrp86 regulate SR protein activity but that it is, in turn, regulated by other splicing factors to control alternative splice site selection.
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Professor, Depts. of Medicine and Biochemistry, Microbiology & Immunology University of Ottawa Career Scientist, Ottawa Regional Cancer Centre Associate Scientist, The Ottawa Hospital Research Institute Telephone: 613-737-7700 ext 6893 Fax: 613-247-3524 Email: [email protected] The control of pre-mRNA splicing by the Clk kinase family
We are studying a family of kinases which we believe provide an interface between intracellular signaling networks and the post-transcriptional mechanism of mRNA splicing. We are performing a structure:function analysis of the three Clk family members to identify domains in the three proteins which are involved in regulating splicing. Using homologous recombination we are generating null strains of mice which are lacking one, two or all three Clk genes. The Clk kinases all possess dual specificity kinase activity and yeast expression systems are being used to produce large amounts of the kinase to perform a detailed analysis of the sites of serine, threonine and tyrosine autophosphorylation within the kinase.Annotated Interactions
No annotated interactions