title: The alternatively-included 11a sequence modifies the effects of Mena on actin cytoskeletal organization and cell behavior.
abstract: During tumor progression, alternative splicing gives rise to different Mena protein isoforms. We analyzed how Mena11a, an isoform enriched in epithelia and epithelial-like cells, affects Mena-dependent regulation of actin dynamics and cell behavior. While other Mena isoforms promote actin polymerization and drive membrane protrusion, we find that Mena11a decreases actin polymerization and growth factor-stimulated membrane protrusion at lamellipodia. Ectopic Mena11a expression slows mesenchymal-like cell motility, while isoform-specific depletion of endogenous Mena11a in epithelial-like tumor cells perturbs cell:cell junctions and increases membrane protrusion and overall cell motility. Mena11a can dampen membrane protrusion and reduce actin polymerization in the absence of other Mena isoforms, indicating that it is not simply an inactive Mena isoform. We identify a phosphorylation site within 11a that is required for some Mena11a-specific functions. RNA-seq data analysis from patient cohorts demonstrates that the difference between mRNAs encoding constitutive Mena sequences and those containing the 11a exon correlates with metastasis in colorectal cancer, suggesting that 11a exon exclusion contributes to invasive phenotypes and leads to poor clinical outcomes.
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Balsamo
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Chandrani
authors.initials: C
authors.lastname: Mondal
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Carmona
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Leslie M
authors.initials: LM
authors.lastname: McClain
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Daisy N
authors.initials: DN
authors.lastname: Riquelme
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Jenny
authors.initials: J
authors.lastname: Tadros
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Duan
authors.initials: D
authors.lastname: Ma
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Eliza
authors.initials: E
authors.lastname: Vasile
authors.affiliation: Department of Anatomy and Structural Biology, Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Condeelis
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Lauffenburger
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Frank B
authors.initials: FB
authors.lastname: Gertler
mesh_terms: D008841:Actin Cytoskeleton; D017398:Alternative Splicing; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002448:Cell Adhesion; D002450:Cell Communication; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D015179:Colorectal Neoplasms / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D008168:Lung / Q000196:embryology / Q000378:metabolism; D061986:MCF-7 Cells; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D010766:Phosphorylation; D011554:Pseudopodia / Q000473:pathology; D011650:Pulmonary Alveoli / Q000378:metabolism; D012867:Skin / Q000196:embryology / Q000378:metabolism; D016896:Treatment Outcome; D015854:Up-Regulation; D014945:Wound Healing
chemical_list: D015415:Biomarkers; D003598:Cytoskeletal Proteins; C511939:Enah protein, human; C102176:Enah protein, mouse; D008840:Microfilament Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors