Comparative genome analysis of cortactin and HS1: the significance of the F-actin binding repeat domain.
BACKGROUND
In human carcinomas, overexpression of cortactin correlates with poor prognosis. Cortactin is an F-actin-binding protein involved in cytoskeletal rearrangements and cell migration by promoting actin-related protein (Arp)2/3 mediated actin polymerization. It shares a high amino acid sequence and structural similarity to hematopoietic lineage cell-specific protein 1 (HS1) although their functions differ considerable. In this manuscript we describe the genomic organization of these two genes in a variety of species by a combination of cloning and database searches. Based on our analysis, we predict the genesis of the actin-binding repeat domain during evolution.


RESULTS
Cortactin homologues exist in sponges, worms, shrimps, insects, urochordates, fishes, amphibians, birds and mammalians, whereas HS1 exists in vertebrates only, suggesting that both genes have been derived from an ancestor cortactin gene by duplication. In agreement with this, comparative genome analysis revealed very similar exon-intron structures and sequence homologies, especially over the regions that encode the characteristic highly conserved F-actin-binding repeat domain. Cortactin splice variants affecting this F-actin-binding domain were identified not only in mammalians, but also in amphibians, fishes and birds. In mammalians, cortactin is ubiquitously expressed except in hematopoietic cells, whereas HS1 is mainly expressed in hematopoietic cells. In accordance with their distinct tissue specificity, the putative promoter region of cortactin is different from HS1.


CONCLUSIONS
Comparative analysis of the genomic organization and amino acid sequences of cortactin and HS1 provides inside into their origin and evolution. Our analysis shows that both genes originated from a gene duplication event and subsequently HS1 lost two repeats, whereas cortactin gained one repeat. Our analysis genetically underscores the significance of the F-actin binding domain in cytoskeletal remodeling, which is of importance for the major role of HS1 in apoptosis and for cortactin in cell migration.
van Rossum
Agnes G S H
AG
Department of Pathology, Leiden University Medical Center, Albinusdreef 2, 2300 RC, Leiden, The Netherlands. a.van.rossum@ioi.knaw.nl
Schuuring-Scholtes
Ellen
E
van Buuren-van Seggelen
Vera
V
Kluin
Philip M
PM
Schuuring
Ed
E
D051377:Actin-Related Protein 2 / Q000737:chemistry; D051378:Actin-Related Protein 3 / Q000737:chemistry; D000199:Actins / Q000737:chemistry*; D048868:Adaptor Proteins, Signal Transducing; D017398:Alternative Splicing; D000818:Animals; D017209:Apoptosis; D001798:Blood Proteins / Q000737:chemistry*; D045744:Cell Line, Tumor; D019070:Cell Lineage; D002465:Cell Movement; D003001:Cloning, Molecular; D051356:Cortactin / Q000737:chemistry*; D003599:Cytoskeleton / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D019992:Databases as Topic; D016208:Databases, Factual; D030541:Databases, Genetic; D019143:Evolution, Molecular; D005091:Exons; D020440:Gene Duplication; D016678:Genome; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D007438:Introns; D008957:Models, Genetic; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry
D051377:Actin-Related Protein 2; D051378:Actin-Related Protein 3; D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D001798:Blood Proteins; D051356:Cortactin; D018076:DNA, Complementary; C061909:HCLS1 protein, human; D011506:Proteins