Document Detail

FAM123A binds to microtubules and inhibits the guanine nucleotide exchange factor ARHGEF2 to decrease actomyosin contractility.
MedLine Citation:
PMID:  22949735     Owner:  NLM     Status:  MEDLINE    
The FAM123 gene family comprises three members: FAM123A, the tumor suppressor WTX (also known as FAM123B), and FAM123C. WTX is required for normal development and causally contributes to human disease, in part through its regulation of β-catenin-dependent WNT signaling. The roles of FAM123A and FAM123C in signaling, cell behavior, and human disease remain less understood. We defined and compared the protein-protein interaction networks for each member of the FAM123 family by affinity purification and mass spectrometry. Protein localization and functional studies suggest that the FAM123 family members have conserved and divergent cellular roles. In contrast to WTX and FAM123C, we found that microtubule-associated proteins were enriched in the FAM123A protein interaction network. FAM123A interacted with and tracked with the plus end of dynamic microtubules. Domain interaction experiments revealed a "SKIP" amino acid motif in FAM123A that mediated interaction with the microtubule tip tracking proteins end-binding protein 1 (EB1) and EB3--and therefore with microtubules. Cells depleted of FAM123A showed compartment-specific effects on microtubule dynamics, increased actomyosin contractility, larger focal adhesions, and decreased cell migration. These effects required binding of FAM123A to and inhibition of the guanine nucleotide exchange factor ARHGEF2, a microtubule-associated activator of RhoA. Together, these data suggest that the SKIP motif enables FAM123A, but not the other FAM123 family members, to bind to EB proteins, localize to microtubules, and coordinate microtubule dynamics and actomyosin contractility.
Priscila F Siesser; Marta Motolese; Matthew P Walker; Dennis Goldfarb; Kelly Gewain; Feng Yan; Rima M Kulikauskas; Andy J Chien; Linda Wordeman; Michael B Major
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-09-04
Journal Detail:
Title:  Science signaling     Volume:  5     ISSN:  1937-9145     ISO Abbreviation:  Sci Signal     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-09-05     Completed Date:  2013-01-14     Revised Date:  2014-11-12    
Medline Journal Info:
Nlm Unique ID:  101465400     Medline TA:  Sci Signal     Country:  United States    
Other Details:
Languages:  eng     Pagination:  ra64     Citation Subset:  IM    
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MeSH Terms
Actomyosin / metabolism*
Adaptor Proteins, Signal Transducing / genetics*,  metabolism*
Amino Acid Motifs / genetics
Chromatography, Affinity
Focal Adhesions / metabolism
Guanine Nucleotide Exchange Factors / antagonists & inhibitors*
Mass Spectrometry
Microtubule-Associated Proteins / metabolism*
Microtubules / metabolism*
Protein Interaction Mapping
Rho Guanine Nucleotide Exchange Factors
Tumor Suppressor Proteins / genetics*,  metabolism*
Grant Support
1-DP2-OD007149-01/OD/NIH HHS; DP2 OD007149/OD/NIH HHS; GM69429/GM/NIGMS NIH HHS; P30 CA016086/CA/NCI NIH HHS; //Howard Hughes Medical Institute
Reg. No./Substance:
0/ARHGEF2 protein, human; 0/Adaptor Proteins, Signal Transducing; 0/FAM123A protein, human; 0/Guanine Nucleotide Exchange Factors; 0/MAPRE1 protein, human; 0/Microtubule-Associated Proteins; 0/Rho Guanine Nucleotide Exchange Factors; 0/Tumor Suppressor Proteins; 9013-26-7/Actomyosin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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