Regulation of alternative splicing by reversible protein phosphorylation

被引:191
作者
Stamm, Stefan [1 ]
机构
[1] Univ Kentucky, Coll Med, Dept Mol & Cellular Biochem, Lexington, KY 40536 USA
关键词
D O I
10.1074/jbc.R700034200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The vast majority of human protein-coding genes are subject to alternative splicing, which allows the generation of more than one protein isoform from a single gene. Cells can change alternative splicing patterns in response to a signal, which creates protein variants with different biological properties. The selection of alternative splice sites is governed by the dynamic formation of protein complexes on the processed pre-mRNA. A unique set of these splicing regulatory proteins assembles on different pre-mRNAs, generating a "splicing" or "messenger ribonucleoprotein code" that determines exon recognition. By influencing protein/protein and protein/RNA interactions, reversible protein phosphorylation modulates the assembly of regulatory proteins on pre-mRNA and therefore contributes to the splicing code. Studies of the serine/arginine-rich protein class of regulators identified different kinases and protein phosphatase 1 as the molecules that control reversible phosphorylation, which controls not only splice site selection, but also the localization of serine/ arginine-rich proteins and mRNA export. The involvement of protein phosphatase 1 explains why second messengers like cAMP and ceramide that control the activity of this phosphatase influence alternative splicing. The emerging mechanistic links between splicing regulatory proteins and known signal transduction pathways now allow in detail the understanding how cellular signals modulate gene expression by influencing alternative splicing. This knowledge can be applied to human diseases that are caused by the selection of wrong splice sites.
引用
收藏
页码:1223 / 1227
页数:5
相关论文
共 69 条
[1]   Regulation of heterogenous nuclear ribonucleoprotein A1 transport by phosphorylation in cells stressed by osmotic shock [J].
Allemand, E ;
Guil, S ;
Myers, M ;
Moscat, J ;
Cáceres, JF ;
Krainer, AR .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (10) :3605-3610
[2]   Alternative splicing regulation by interaction of phosphatase PP2Cγ with nucleic acid-binding protein YB-1 [J].
Allemand, Eric ;
Hastings, Michelle L. ;
Murray, Michael V. ;
Myers, Michael P. ;
Krainer, Adrian R. .
NATURE STRUCTURAL & MOLECULAR BIOLOGY, 2007, 14 (07) :630-638
[3]   Processive phosphorylation of alternative splicing factor/splicing factor 2 [J].
Aubol, BE ;
Chakrabarti, S ;
Ngo, J ;
Shaffer, J ;
Nolen, B ;
Fu, XD ;
Ghosh, G ;
Adams, JA .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (22) :12601-12606
[4]   The protein phosphatase-1 regulator NIPP1 is also a splicing factor involved in a late step of spliceosome assembly [J].
Beullens, M ;
Bollen, M .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (22) :19855-19860
[5]   Concerted regulation of nuclear and cytoplasmic activities of SR proteins by AKT [J].
Blaustein, M ;
Pelisch, F ;
Tanos, T ;
Muñoz, MJ ;
Wengier, D ;
Quadrana, L ;
Sanford, JR ;
Muschietti, JP ;
Kornblihtt, AR ;
Cáceres, JF ;
Coso, OA ;
Srebrow, A .
NATURE STRUCTURAL & MOLECULAR BIOLOGY, 2005, 12 (12) :1037-1044
[6]   Signals, pathways and splicing regulation [J].
Blaustein, Matias ;
Pelisch, Federico ;
Srebrow, Anabella .
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY, 2007, 39 (11) :2031-2048
[7]   The role of protein phosphatase-1 in insulin action [J].
Brady, MJ ;
Saltiel, AR .
RECENT PROGRESS IN HORMONE RESEARCH, VOL 56, 2001, 56 :157-173
[8]  
Cao WH, 1997, RNA, V3, P1456
[9]   PROTEIN PHOSPHATASE-1 CAN MODULATE ALTERNATIVE 5' SPLICE-SITE SELECTION IN A HELA SPLICING EXTRACT [J].
CARDINALI, B ;
COHEN, PTW ;
LAMOND, AI .
FEBS LETTERS, 1994, 352 (03) :276-280
[10]   Functional diversity of protein phosphatase-1, a cellular economizer and reset button [J].
Ceulemans, H ;
Bollen, M .
PHYSIOLOGICAL REVIEWS, 2004, 84 (01) :1-39