Translational control of C-terminal Src kinase (Csk) expression by PRL3 phosphatase.
Phosphatase of regenerating liver 3 (PRL3) is up-regulated in cancer metastases. However, little is known of PRL3-mediated cellular signaling pathways. We previously reported that elevated PRL3 expression increases Src kinase activity, which likely contributes to the increased tumorigenesis and metastasis potential of PRL3. PRL3-induced Src activation is proposed to be indirect through down-regulation of Csk, a negative regulator of Src. Given the importance of PRL3 in tumor metastasis and the role of Csk in controlling Src activity, we addressed the mechanism by which PRL3 mediates Csk down-regulation. PRL3 is shown to exert a negative effect on Csk protein synthesis, rather than regulation of Csk mRNA levels or protein turnover. Interestingly, the preferential decrease in Csk protein synthesis is a consequence of increased eIF2 phosphorylation resulting from PRL3 expression. Reduced Csk synthesis also occurs in response to cellular stress that induces eIF2 phosphorylation, indicating that this regulatory mechanism may occur in response to a wider spectrum of cellular conditions known to direct translational control. Thus, we have uncovered a previously uncharacterized role for PRL3 in the gene-specific translational control of Csk expression.
Liang
Fubo
F
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Luo
Yong
Y
Dong
Yuanshu
Y
Walls
Chad D
CD
Liang
Jiao
J
Jiang
Hao-Yuan
HY
Sanford
Jeremy R
JR
Wek
Ronald C
RC
Zhang
Zhong-Yin
ZY
D000081247:CSK Tyrosine-Protein Kinase; D002460:Cell Line; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005786:Gene Expression Regulation; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008954:Models, Biological; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000378:metabolism / Q000502:physiology*; D010447:Peptide Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D011132:Polyribosomes / Q000378:metabolism; D014176:Protein Biosynthesis; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000378:metabolism; D019061:src-Family Kinases
D015852:Eukaryotic Initiation Factor-2; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; C484730:PTP4A3 protein, human; D017027:Protein Tyrosine Phosphatases; D010447:Peptide Hydrolases