Emerging links between CDK cell cycle regulators and Wnt signaling.

Wnt/beta-catenin signaling controls many aspects of cell behavior throughout development and in adults. One of its best-known and cancer-relevant functions is to stimulate cell proliferation. Recent work has implicated Wnt components in regulating mitotic events, suggesting that the cell cycle and Wnt signaling are directly linked. This concept has now been substantially strengthened with the finding that the mitotic CDK14/cyclin Y complex promotes Wnt signaling through phosphorylation of the LRP6 co-receptor, a key regulatory nexus in the Wnt/beta-catenin pathway. Thus, an unexpectedly tight collaboration between the mitotic cell cycle machinery and Wnt signaling is emerging, suggesting that this pathway might orchestrate mitotic processes.

[1]  Dianqing Wu,et al.  Wnt3a-Mediated Formation of Phosphatidylinositol 4,5-Bisphosphate Regulates LRP6 Phosphorylation , 2008, Science.

[2]  H. Varmus,et al.  Mouse mammary tumor virus infection accelerates mammary carcinogenesis in Wnt-1 transgenic mice by insertional activation of int-2/Fgf-3 and hst/Fgf-4. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[3]  S. Byers,et al.  Exogenous Expression of β-Catenin Regulates Contact Inhibition, Anchorage-Independent Growth, Anoikis, and Radiation-Induced Cell Cycle Arrest , 1999, The Journal of cell biology.

[4]  Christof Niehrs,et al.  Regulation of Lrp6 phosphorylation , 2010, Cellular and Molecular Life Sciences.

[5]  M. Barbacid,et al.  Mammalian cyclin-dependent kinases. , 2005, Trends in biochemical sciences.

[6]  R. J. Hill,et al.  C. elegans LIN-18 Is a Ryk Ortholog and Functions in Parallel to LIN-17/Frizzled in Wnt Signaling , 2004, Cell.

[7]  Amy E. Shyer,et al.  Kif3a constrains β-catenin-dependent Wnt signalling through dual ciliary and non-ciliary mechanisms , 2008, Nature Cell Biology.

[8]  J. Behrens,et al.  CIN by WNT: Growth Pathways, Mitotic Control and Chromosomal Instability in Cancer , 2006, Cell cycle.

[9]  Nam-Chul Ha,et al.  Direct Inhibition of GSK3β by the Phosphorylated Cytoplasmic Domain of LRP6 in Wnt/β-Catenin Signaling , 2008, PloS one.

[10]  Liaoyuan A. Hu,et al.  Dishevelled 2 Recruits ß-Arrestin 2 to Mediate Wnt5A-Stimulated Endocytosis of Frizzled 4 , 2003, Science.

[11]  P. Casey,et al.  beta-Catenin is a Nek2 substrate involved in centrosome separation. , 2008, Genes & development.

[12]  Christof Niehrs,et al.  Wnt Induces LRP6 Signalosomes and Promotes Dishevelled-Dependent LRP6 Phosphorylation , 2007, Science.

[13]  R. Nusse,et al.  Wnt and FGF signals interact to coordinate growth with cell fate specification during limb development , 2008, Development.

[14]  L. Solnica-Krezel,et al.  Regulation of convergence and extension movements during vertebrate gastrulation by the Wnt/PCP pathway. , 2009, Seminars in cell & developmental biology.

[15]  Jeremy Nathans,et al.  A new member of the frizzled family from Drosophila functions as a Wingless receptor , 1996, Nature.

[16]  Yoshiki Higuchi,et al.  The DIX domain of Dishevelled confers Wnt signaling by dynamic polymerization , 2007, Nature Structural &Molecular Biology.

[17]  M. Mlodzik,et al.  A Quest for the Mechanism Regulating Global Planar Cell Polarity of Tissues , 2022 .

[18]  Xi He,et al.  LDL receptor-related proteins 5 and 6 in Wnt/β-catenin signaling: Arrows point the way , 2004, Development.

[19]  D. Ambrosetti,et al.  Mechanisms underlying differential responses to FGF signaling. , 2005, Cytokine & growth factor reviews.

[20]  J. Abreu,et al.  Inhibition of GSK3 Phosphorylation of β-Catenin via Phosphorylated PPPSPXS Motifs of Wnt Coreceptor LRP6 , 2009, PloS one.

[21]  J. Harper,et al.  A premature-termination mutation in the Mus musculus cyclin-dependent kinase 3 gene. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[22]  Xi He,et al.  Control of β-Catenin Phosphorylation/Degradation by a Dual-Kinase Mechanism , 2002, Cell.

[23]  Bert Hobmayer,et al.  Wnt/β-Catenin and noncanonical Wnt signaling interact in tissue evagination in the simple eumetazoan Hydra , 2009, Proceedings of the National Academy of Sciences.

[24]  Thaddeus S. Stappenbeck,et al.  Response of small intestinal epithelial cells to acute disruption of cell division through CDC25 deletion , 2009, Proceedings of the National Academy of Sciences.

[25]  T. Holstein Wnt signaling in cnidarians. , 2008, Methods in molecular biology.

[26]  D. Hogness,et al.  The L63 gene is necessary for the ecdysone-induced 63E late puff and encodes CDK proteins required for Drosophila development. , 2000, Developmental biology.

[27]  T. Hunt,et al.  Cyclin B2-null mice develop normally and are fertile whereas cyclin B1-null mice die in utero. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[28]  Steven J. Marygold,et al.  Armadillo levels are reduced during mitosis in Drosophila , 2003, Mechanisms of Development.

[29]  Frederick R. Cross,et al.  Positive feedback of G1 cyclins ensures coherent cell cycle entry , 2008, Nature.

[30]  Xi He,et al.  A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation , 2005, Nature.

[31]  Alan Hall,et al.  Wnt signaling pathways meet Rho GTPases. , 2009, Genes & development.

[32]  P. Gönczy,et al.  Coupling the cell cycle to development , 2009, Development.

[33]  M. Caron,et al.  G Protein-coupled Receptor Kinases Phosphorylate LRP6 in the Wnt Pathway , 2009, The Journal of Biological Chemistry.

[34]  R. Nusse,et al.  Wnts as ligands: processing, secretion and reception , 2006, Oncogene.

[35]  R. Coffey,et al.  Lrp6 is required for convergent extension during Xenopus gastrulation , 2007, Development.

[36]  A. Kikuchi,et al.  Axin localizes to the centrosome and is involved in microtubule nucleation , 2009, EMBO reports.

[37]  Jie J. Zheng,et al.  Direct binding of the PDZ domain of Dishevelled to a conserved internal sequence in the C-terminal region of Frizzled. , 2003, Molecular cell.

[38]  R. Moon,et al.  Beta-catenin-independent Wnt pathways: signals, core proteins, and effectors. , 2008, Methods in molecular biology.

[39]  Xi He,et al.  Wnt Signal Amplification via Activity, Cooperativity, and Regulation of Multiple Intracellular PPPSP Motifs in the Wnt Co-receptor LRP6* , 2008, Journal of Biological Chemistry.

[40]  D. Rickman,et al.  Apc tumor suppressor gene is the "zonation-keeper" of mouse liver. , 2006, Developmental cell.

[41]  William C. Skarnes,et al.  An LDL-receptor-related protein mediates Wnt signalling in mice , 2000, Nature.

[42]  Akira Kikuchi,et al.  LRP6 is internalized by Dkk1 to suppress its phosphorylation in the lipid raft and is recycled for reuse , 2010, Journal of Cell Science.

[43]  D O Morgan,et al.  Cyclin-dependent kinases: engines, clocks, and microprocessors. , 1997, Annual review of cell and developmental biology.

[44]  Michael Boutros,et al.  Regulation of Wnt protein secretion and its role in gradient formation , 2008, EMBO reports.

[45]  M. Boutros,et al.  Cell cycle control of wnt receptor activation. , 2009, Developmental cell.

[46]  Tao Yang,et al.  Cyclin Y, a novel membrane‐associated cyclin, interacts with PFTK1 , 2009, FEBS letters.

[47]  T. Misteli,et al.  Condensed mitotic chromatin is accessible to transcription factors and chromatin structural proteins , 2005, The Journal of cell biology.

[48]  Andrew Tomlinson,et al.  arrow encodes an LDL-receptor-related protein essential for Wingless signalling , 2000, Nature.

[49]  K. Nakayama,et al.  Ubiquitin ligases: cell-cycle control and cancer , 2006, Nature Reviews Cancer.

[50]  J. Hardin,et al.  Wnt-dependent spindle polarization in the early C. elegans embryo. , 2006, Seminars in cell & developmental biology.

[51]  S. Vilaró,et al.  Beta-catenin regulation during the cell cycle: implications in G2/M and apoptosis. , 2003, Molecular biology of the cell.

[52]  W. Song,et al.  Modulation of β-Catenin Phosphorylation/Degradation by Cyclin-dependent Kinase 2* , 2004, Journal of Biological Chemistry.

[53]  Wange Lu,et al.  Mammalian Ryk Is a Wnt Coreceptor Required for Stimulation of Neurite Outgrowth , 2004, Cell.

[54]  B. Gabrielli,et al.  Cyclin A/cdk2 Regulates Adenomatous Polyposis Coli-dependent Mitotic Spindle Anchoring* , 2009, The Journal of Biological Chemistry.

[55]  D. van der Kooy,et al.  Ciliary margin transdifferentiation from neural retina is controlled by canonical Wnt signaling. , 2007, Developmental biology.

[56]  T. Senga,et al.  A novel role of phospho-β-catenin in microtubule regrowth at centrosome , 2007, Oncogene.

[57]  Xin Wang,et al.  Functional characterization of human PFTK1 as a cyclin-dependent kinase , 2007, Proceedings of the National Academy of Sciences.

[58]  M. Katoh,et al.  Cross-talk of WNT and FGF signaling pathways at GSK3ß to regulate ß-catenin and SNAIL signaling cascades , 2006, Cancer biology & therapy.

[59]  Hans Clevers,et al.  Wnt/β-Catenin Signaling in Development and Disease , 2006, Cell.

[60]  B. Doble,et al.  Glycogen synthase kinase-3--an overview of an over-achieving protein kinase. , 2006, Current drug targets.

[61]  John B. Thomas,et al.  Wnt-mediated axon guidance via the Drosophila Derailed receptor , 2003, Nature.

[62]  E. Cisneros,et al.  Cell cycle control of Notch signaling and the functional regionalization of the neuroepithelium during vertebrate neurogenesis. , 2009, The International journal of developmental biology.

[63]  Akira Kikuchi,et al.  Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK‐3β and β‐catenin and promotes GSK‐3β‐dependent phosphorylation of β‐catenin , 1998 .

[64]  B. Yoder,et al.  The Primary Cilium as a Complex Signaling Center , 2009, Current Biology.

[65]  T. Stearns,et al.  Adenomatous polyposis coli and EB1 localize in close proximity of the mother centriole and EB1 is a functional component of centrosomes , 2004, Journal of Cell Science.

[66]  Ethan Lee,et al.  LRP6 transduces a canonical Wnt signal independently of Axin degradation by inhibiting GSK3's phosphorylation of β-catenin , 2008, Proceedings of the National Academy of Sciences of the United States of America.

[67]  B. Williams,et al.  Multiple PPPS/TP motifs act in a combinatorial fashion to transduce Wnt signaling through LRP6 , 2008, FEBS letters.

[68]  Pierre Dubus,et al.  Cdk1 is sufficient to drive the mammalian cell cycle , 2007, Nature.

[69]  K. Kaplan,et al.  The role of APC in mitosis and in chromosome instability. , 2009, Advances in experimental medicine and biology.

[70]  Riccardo Fodde,et al.  Wnt/β-catenin signaling in cancer stemness and malignant behavior , 2007 .

[71]  U. Surana,et al.  Regulation of centrosome separation in yeast and vertebrates: common threads. , 2009, Trends in cell biology.

[72]  David O. Morgan,et al.  Positive feedback sharpens the anaphase switch , 2008, Nature.

[73]  Christof Niehrs,et al.  Casein kinase 1 γ couples Wnt receptor activation to cytoplasmic signal transduction , 2005, Nature.

[74]  J Mao,et al.  Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway. , 2001, Molecular cell.

[75]  Akira Kikuchi,et al.  Selective Activation Mechanisms of Wnt Signaling Pathways Review , 2022 .

[76]  J. Klingensmith,et al.  The dishevelled protein is modified by wingless signaling in Drosophila. , 1995, Genes & development.

[77]  Nam-Chul Ha,et al.  The role of the Ser/Thr cluster in the phosphorylation of PPPSP motifs in Wnt coreceptors. , 2009, Biochemical and biophysical research communications.

[78]  P. Kaldis,et al.  Mammalian cell-cycle regulation: several Cdks, numerous cyclins and diverse compensatory mechanisms , 2009, Oncogene.

[79]  Jane Sun,et al.  Wnt and beyond Wnt: multiple mechanisms control the transcriptional property of beta-catenin. , 2008, Cellular signalling.

[80]  W. Song,et al.  Modulation of β-catenin by cyclin-dependent kinase 6 in Wnt-stimulated cells , 2007 .

[81]  W. Song,et al.  Cyclin-dependent kinase 2 regulates the interaction of Axin with β-catenin , 2004 .

[82]  Chika Yokota,et al.  Initiation of Wnt signaling: control of Wnt coreceptor Lrp6 phosphorylation/activation via frizzled, dishevelled and axin functions , 2007, Development.

[83]  I. Hiratani,et al.  The Xenopus receptor tyrosine kinase Xror2 modulates morphogenetic movements of the axial mesoderm and neuroectoderm via Wnt signaling. , 2002, Development.

[84]  Li-Huei Tsai,et al.  Cyclin-dependent kinases: a family portrait , 2009, Nature Cell Biology.

[85]  Yoichi Kato,et al.  LDL-receptor-related proteins in Wnt signal transduction , 2000, Nature.

[86]  James E. Ferrell,et al.  Systems biology: On the cell cycle and its switches , 2008, Nature.

[87]  A. Stella,et al.  APC is essential for targeting phosphorylated beta-catenin to the SCFbeta-TrCP ubiquitin ligase. , 2008, Molecular cell.

[88]  Y. Bellaïche,et al.  Cell division orientation and planar cell polarity pathways. , 2009, Seminars in cell & developmental biology.

[89]  J. Behrens,et al.  Conductin/axin2 and Wnt signalling regulates centrosome cohesion , 2010, EMBO reports.

[90]  Chris Q. Doe,et al.  Spindle orientation during asymmetric cell division , 2009, Nature Cell Biology.

[91]  A. Antipova,et al.  Interaction of Dishevelled and XenopusAxin-Related Protein Is Required for Wnt Signal Transduction , 2000, Molecular and Cellular Biology.

[92]  S. Sokol,et al.  Xenopus axin‐related protein: A link between its centrosomal localization and function in the Wnt/β‐catenin pathway , 2009, Developmental dynamics : an official publication of the American Association of Anatomists.

[93]  Wei Hsu,et al.  The Mouse Fused Locus Encodes Axin, an Inhibitor of the Wnt Signaling Pathway That Regulates Embryonic Axis Formation , 1997, Cell.

[94]  W. Birchmeier,et al.  Aberrant Wnt/beta-catenin signaling can induce chromosomal instability in colon cancer. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[95]  Xi He,et al.  Wnt/beta-catenin signaling: components, mechanisms, and diseases. , 2009, Developmental cell.

[96]  D. Kimelman,et al.  β-Catenin destruction complex: insights and questions from a structural perspective , 2006, Oncogene.

[97]  N. Hayashi,et al.  Myristoylation of p39 and p35 is a determinant of cytoplasmic or nuclear localization of active cycline‐dependent kinase 5 complexes , 2008, Journal of neurochemistry.