title: A mitotic kinase scaffold depleted in testicular seminomas impacts spindle orientation in germ line stem cells.
abstract: Correct orientation of the mitotic spindle in stem cells underlies organogenesis. Spindle abnormalities correlate with cancer progression in germ line-derived tumors. We discover a macromolecular complex between the scaffolding protein Gravin/AKAP12 and the mitotic kinases, Aurora A and Plk1, that is down regulated in human seminoma. Depletion of Gravin correlates with an increased mitotic index and disorganization of seminiferous tubules. Biochemical, super-resolution imaging, and enzymology approaches establish that this Gravin scaffold accumulates at the mother spindle pole during metaphase. Manipulating elements of the Gravin-Aurora A-Plk1 axis prompts mitotic delay and prevents appropriate assembly of astral microtubules to promote spindle misorientation. These pathological responses are conserved in seminiferous tubules from Gravin(-/-) mice where an overabundance of Oct3/4 positive germ line stem cells displays randomized orientation of mitotic spindles. Thus, we propose that Gravin-mediated recruitment of Aurora A and Plk1 to the mother (oldest) spindle pole contributes to the fidelity of symmetric cell division.
authors.affiliation: Department of Pharmacology, Howard Hughes Medical Institute, University of Washington, Seattle, United States.|Department of Cell and Developmental Biology, State University of New York Upstate Medical University, Syracuse, United States.
authors.forename: Heidi
authors.initials: H
authors.lastname: Hehnly
authors.affiliation: Department of Pharmacology, Howard Hughes Medical Institute, University of Washington, Seattle, United States.
authors.forename: David
authors.initials: D
authors.lastname: Canton
authors.affiliation: Department of Pharmacology, Howard Hughes Medical Institute, University of Washington, Seattle, United States.
authors.forename: Paula
authors.initials: P
authors.lastname: Bucko
authors.affiliation: Department of Pharmacology, Howard Hughes Medical Institute, University of Washington, Seattle, United States.
authors.forename: Lorene K
authors.initials: LK
authors.lastname: Langeberg
authors.affiliation: Department of Pharmacology, Howard Hughes Medical Institute, University of Washington, Seattle, United States.
authors.forename: Leah
authors.initials: L
authors.lastname: Ogier
authors.affiliation: Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, United States.
authors.forename: Irwin
authors.initials: I
authors.lastname: Gelman
authors.affiliation: Department of Physiology and Biophysics, University of Washington, Seattle, United States.
authors.forename: L Fernando
authors.initials: LF
authors.lastname: Santana
authors.affiliation: Department of Physiology and Biophysics, University of Washington, Seattle, United States.
authors.forename: Linda
authors.initials: L
authors.lastname: Wordeman
authors.affiliation: Department of Pharmacology, Howard Hughes Medical Institute, University of Washington, Seattle, United States.
authors.forename: John D
authors.initials: JD
authors.lastname: Scott
mesh_terms: D054758:A Kinase Anchor Proteins / Q000378:metabolism*; D000818:Animals; D064096:Aurora Kinase A / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002455:Cell Division; D005854:Germ Cells / Q000502:physiology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D018239:Seminoma / Q000473:pathology; D008941:Spindle Apparatus / Q000378:metabolism*; D013234:Stem Cells / Q000502:physiology*; D000097869:Polo-Like Kinase 1
chemical_list: D054758:A Kinase Anchor Proteins; D064096:Aurora Kinase A; D018797:Cell Cycle Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1; C491162:AKAP12 protein, human; C576917:AURKA protein, human
keywords: biochemistry; cell biology; cell regulation; human; mitotic spindle; mouse; protein kinase; signal transduction; testicular cancer