title: Evolutionary and molecular facts link the WWC protein family to Hippo signaling.
abstract: The scaffolding protein KIBRA (also called WWC1) is involved in the regulation of important intracellular transport processes and the establishment of cell polarity. Furthermore, KIBRA/WWC1 is an upstream regulator of the Hippo signaling pathway that controls cell proliferation and organ size in animals. KIBRA/WWC1 represents only one member of the WWC protein family that also includes the highly similar proteins WWC2 and WWC3. Although the function of KIBRA/WWC1 was studied intensively in cells and animal models, the importance of WWC2 and WWC3 was not yet elucidated. Here, we describe evolutionary, molecular, and functional aspects of the WWC family. We show that the WWC genes arose in the ancestor of bilateral animals (clades such as insects and vertebrates) from a single founder gene most similar to the present KIBRA/WWC1-like sequence of Drosophila. This situation was still maintained until the common ancestor of lancelet and vertebrates. In fish, a progenitor-like sequence of mammalian KIBRA/WWC1 and WWC2 is expressed together with WWC3. Finally, in all tetrapods, the three family members, KIBRA/WWC1, WWC2, and WWC3, are found, except for a large genomic deletion including WWC3 in Mus musculus. At the molecular level, the highly conserved WWC proteins share a similar primary structure, the ability to form homo- and heterodimers and the interaction with a common set of binding proteins. Furthermore, all WWC proteins negatively regulate cell proliferation and organ growth due to a suppression of the transcriptional activity of YAP, the major effector of the Hippo pathway.
authors.affiliation: Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology, University Hospital Muenster, Muenster, Germany.
authors.forename: Dirk Oliver
authors.initials: DO
authors.lastname: Wennmann
authors.affiliation: Institute of Experimental Pathology, ZMBE, University of Muenster, Muenster, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schmitz
authors.affiliation: Department of Psychiatry, Molecular Neurobiology, Ludwig Maximilians University, Munich, Germany.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Wehr
authors.affiliation: Institute for Molecular and Cellular Anatomy, University of Regensburg, Regensburg, Germany.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Krahn
authors.affiliation: Institute for Molecular and Cellular Anatomy, University of Regensburg, Regensburg, Germany.
authors.forename: Nora
authors.initials: N
authors.lastname: Koschmal
authors.affiliation: Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology, University Hospital Muenster, Muenster, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Gromnitza
authors.affiliation: Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology, University Hospital Muenster, Muenster, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Schulze
authors.affiliation: Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology, University Hospital Muenster, Muenster, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Weide
authors.affiliation: Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology, University Hospital Muenster, Muenster, Germany.
authors.forename: Anil
authors.initials: A
authors.lastname: Chekuri
authors.affiliation: Institute of Experimental Pathology, ZMBE, University of Muenster, Muenster, GermanyIZKF, University Hospital Muenster, Muenster, Germany.
authors.forename: Boris V
authors.initials: BV
authors.lastname: Skryabin
authors.affiliation: Institute of Medical Biochemistry, ZMBE, University of Muenster, Muenster, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Gerke
authors.affiliation: Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology, University Hospital Muenster, Muenster, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Pavenstädt
authors.affiliation: Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology, University Hospital Muenster, Muenster, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Duning
authors.affiliation: Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology, University Hospital Muenster, Muenster, Germany kremers@uni-muenster.de.
authors.forename: Joachim
authors.initials: J
authors.lastname: Kremerskothen
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation; D019143:Evolution, Molecular; D057809:HEK293 Cells; D006801:Humans; D005810:Multigene Family; D009928:Organ Specificity; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D010802:Phylogeny; D017384:Sequence Deletion; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D010750:Phosphoproteins; D025521:Tumor Suppressor Proteins
keywords: Hippo pathway; KIBRA; LATS kinase; WWC family; YAP; organ size