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Signal Transduction and Gene Regulation in Differentiation and
Development: Roles of Molecular Scaffolds
Craig C. Malbon, Ph.D.
Leading Professor, Director, DMDRC
Ph.D., Case Western Reserve University
Postdoctoral, Brown University
Malbon Lab Page
Transmembrane signaling involves two prominent pathways, one
mediated by G-protein-coupled receptors (GPCR) and other by tyrosine kinases.
GPCRs constitute a superfamily of ~3000 members in the human genome, including
the well-known beta-adrenergic receptors as well as the Frizzleds, which are
receptors for Wnt ligands that function in early development. A central focus
of the laboratory is to understand the mechanisms of signaling that direct
early development, using mouse EC and human ES cells in culture. Currently we
are very interested in the spatial/temporal aspects of signaling and the roles
of scaffold molecules capable of organizing complexes of protein kinases,
phosphatases, adaptor molecules, and GPCRs in signaling. Dishevelled is a primary focus, as it orchestrates dynamic
assemblies of proteins involved in Wnt signaling. We also are interested in
elucidating the biology, structure, and function of a prominent member of the
A-Kinase Anchoring Proteins, AKAP12. We
interrogate these scaffolds using fcs,
BiFC, proteomics and mutagenesis, providing a powerful template for novel research
in this fundamental area of cell and molecular biology.
Dr. Malbon is former Associate Dean, School
of Medicine (1987-1993); founding
University Vice-President for Research (1993-1997); and Vice-Dean for
Scientific Affairs, School
of Medicine (1998-2005)
at Stony Brook. He directs the NIDDK-funded Diabetes & Metabolic Diseases
Research Program (1986-pres.) and efforts aimed at forming principles of
conduct of research in hESCs and areas of ethics, influenced by the work of
Dietrich Bonhoeffer and of Albert Schweitzer.
Most Recent Publications (selected from 240+)
Fegin, M., and
Malbon, C.C. (2007) RGS19 Regulation Wnt/beta-catenin
Signaling Through Inactivation of Galphao.
J. Cell Science 120, in press.
Malbon, C. C.
(2007) AKAPs: Trafficking in G-protein-coupled Receptors and the Proteins that
Regulate Receptor Biology, Curr. Op. Drug
Discovery. 10, in press.
Shumay, E., Tao,
J., Wang, H.-y., and Malbon, C.C. (2007) Lysophosphatidic Acid Regulates
Trafficking of Beta-adrenergic Receptors: the Galpha13/p115RhoGEF/JNK Pathway Stimulates Receptor
Internalization. J. Biol. Chem. 282, 21529-21541.
Tao, J.,
Shumay, E., Wang, H.-y., and Malbon, C.C. (2007) Src-Associated AKAP250:
Regulating Beta2-Adrenergic Receptor Biology. J. Biol. Chem. 282, 6597-6608.
Tao, J.,
Shumay, E., McLaughlin, S., Wang, H.-y., and Malbon, C.C. (2006) Regulation of
AKAP-Membrane Interactions by Calcium. J.
Biol. Chem. 281, 23932-29344.
Yin, D., Gavi, S., Shumay, E., Duell, K., Konopka, J.B., Malbon, C.C.,
and Wang, H.-y. (2006) Yeast G-protein-coupled receptor (Ste2)
Trafficking in Mammalian Cells. J.
Molecular Signaling, 1, 2-8.
Wang, H.-y., Tao,
J., Sumay, E., and Malbon, C.C. (2006) G-protein-coupled
receptor-associated A-kinase anchoring proteins: AKAP79 and AKAP250 (gravin).
Eur. J. Cell Biol. 85,
643-650.
Wang, H.-y., Liu, T., and Malbon, C.C. (2006) Structure-function
analysis of Frizzleds. Cell Signal. 18: 934-41. PDF
Gavi, S., Shumay, E., Wang, H.-y., and Malbon, C.C. (2006) G protein Coupled
Receptors as Substrates for Tyrosine Kinases. Trends in Endocrinology &
Metabolism 17, 46-52. PDF
Malbon, C. C. and Wang, H.-y. (2005) Dishevelled: A Mobile Scaffold
Catalyzing Development. Current Topics in Developmental Biology, 72,
153-166.
Malbon, C.C. and Wang, H.-y (2005) AKAP-based Scaffolds and Insulin Action Cell
Science Rev. 17 (2): 1742-1749.
Malbon, C. C. (2005) G proteins in Development Nature Reviews:
(Molecular Cell Biology), 6, 689-701. PDF
Malbon, C.C. (2005) (Beta) Catenin, Cancer, and G Protein: Not just for
Frizzleds Anymore. Science STKE 292, pe35.
Lee, Y.-n., Malbon, C.C., and Wang, H.-y. (2004)
Galpha13 Signals via p115RhoGEF
Cascades Regulating JNK1 and Primitive Endoderm Formation J. Biol. Chem. 279:
54896-54904. PDF
Gavi, S., Yin, D., Shumay, Malbon, C.C., and
Wang, H.-y. (2004) Insulin-stimulated Sequestration Requires the Integrity of
an SH2 Domain (Y350) and Akt phosphorylation sites (S345,346) of beta2-Adrenergic Receptor.
Endocrinology 146:450-457. PDF
Malbon, C.C., Tao, J., and Wang, H.-y. (2004)
AKAPs and Molecules that Compose their GPCR Signaling Complexes. Biochem. J. 379: 1-9.
PDF
Shumay, E., Gavi, S., Wang, H.Y., and Malbon,
C.C. (2004) Trafficking of Beta2-Adrenergic Receptors: Insulin and Beta agonists Regulate Internalization by Distinct
Cytoskeletal Pathways. J. Cell Science 117:593-600.
PDF
Wang, H.Y. and Malbon, C.C. (2004) Wnt-Frizzled Signaling to G-protein-Coupled
Effectors. Cell. Mol. Life Sci., 61(1):
69-75. PDF
Li, Hong., Malbon, C.C., and Wang, H.-y (2004) Gene Profiling of Frizzled-1
and Frizzled-2 Signaling: Expression of G-protein-coupled Receptor
Chimeras in Mouse F9 Teratocarcinoma Embryonal Cells. Molecular
Pharmacology, 65: 45-55. PDF
Shumay, E., Wang, H.Y., and Malbon, C.C. (2004) Trafficking of
Beta2-Adrenergic Receptors: Insulin and Beta-agonists Regulate
Internalization by Distinct Cytoskeletal Pathways. J. Cell Sci., 117,
593-600. PDF
Tao, J., Wang, H-y., and Malbon, C.C. (2003)betaProtein Kinase A Regulates
AKAP250 (Gravin) Scaffold Binding to the beta2-Adrenergic
Receptor. EMBO Journal, 22(24):6419-29. PDF
Wang, H-y. and Malbon, C.C. (2003). Wnt signaling, Ca+, and
Cyclic GMP: Visualizing Frizzled Functions. Science,
300:1529-1531. PDF
Wang, H-y. and Malbon, C.C. (2003). The Wnt, Calcium, Cyclic GMP
Signaling Pathway. Science STKE Connections Map. (http://stke.sciencemag.org/cgi/cm/stkecm;CMP_12420)
Ahumada, A., Slusarski, D., Liu, X., Moon, R.T., Malbon, C.C. and
Wang, H-y. (2002). Activation of Frizzled-2 signals via cyclic GMP. Science,
298: 2006-2010. PDF
Shumay, E., Song, X., Wang, H-y. and Malbon, C. C. (2002) p60Src
mediates insulin-stimulated sequestration of the beta2-adrenergic
receptor: Molecular Biology of the Cell , 13, 11:
3943-54. PDF
Liu, T., Lee, Y-N., Malbon, C.C. and Wang, H.Y. (2002) Activation of the beta-catenin/Lef-Tcf pathway is obligate for
formation of primitive endoderm by mouse F9 totipotent, teratocarcinoma cells
in response to retinoic acid. J. Biol. Chem., 277,
30887-30891. PDF
Huang, X., Song, X., Wang, H-y. and Malbon, C.C. (2002)
Expression of constitutively-activated Q227L Galphas
in vi:vo: adaptive changes in expression of regulatory subunits of
protein kinase A. Amer. Journal of Physiology, 283(2):C386-95.
PDF
DeCostanzo, A., Wang, H-y., and Malbon, C.C. (2002)The
Frizzled-1/Beta2-Adrenergic Receptor Chimera: Pharmacological Properties of a
Unique G-Protein linked Receptor. Archives of Pharmacology, 365:
341-348.
Doronin, S., Shumay, E., Wang, H-y., and Malbon, C.C. (2002) Akt mediates
sequestration of the beta2-adrenergic
receptor in response to insulin. J. Biol. Chem., 277:15124-15131.
PDF
Doronin, S., Wang, H-y., and Malbon, C.C. (2002) Insulin stimulates
phosphorylation of the beta2-adrenergic receptor
by the insulin receptor, creating a potent feedback inhibitor of its tyrosine
kinase. J. Biol. Chem., 277:10698-10703.
PDF
Wang, H.-y., Kanungo, J., and Malbon, C.C. (2002) Expression of
Galpha13(Q226L) induces P19 stem cells to primitive endoderm via MEKK1/4. J.
Biol. Chem., 277: 3530-3535. PDF
Song X, Tao J, Huang XP, Rosenquist TA, Malbon CC, Wang HY. (2002) Targeted,
regulatable expression of activated heterotrimeric G protein alpha subunits in
transgenic mice. Methods in Enzymology 344:309-318.
Huang XP, Rosenquist TA, Wang HY, Malbon CC. (2002) Inducible,
tissue-specific suppression of heterotrimeric G protein alpha subunits in
vivo. Methods in Enzymology 344:318-327.
Doronin, S., Shumay, E., Wang, H-y. and Malbon, C.C. (2001)Lithium
Suppresses Signaling and Induces Rapid Sequestration of Beta2-Adrenergic
Receptors Biochem. Biophys. Res. Commu., 288:150-155.
Malbon, C.C., Wang, H-y. and Moon, R.T. (2001) Wnt Signaling and
Hetertrimeric G-proteins: Strange Bedfellows or a Classic Romance. Biochem.
Biophys. Res. Commu. 287:589-593.
Song, X., Zheng, X., Malbon, C.C. and Wang, H-y. (2001) Galphai2 enhances in vivo activation of
and insulin signaling to GLUT4. J. Biol. Chem., 276:
34651-34658. PDF
Tao, J., Malbon, C.C. and Wang, H-y. (2001) Insulin stimulates
tyrosine phosphorylation and inactivation of protein tyrosine phosphatase 1B in
vivo. J. Biol. Chem., 276:29520-29525. PDF
Tao, J., Malbon, C.C. and Wang, H-y. (2001) Galphai2 enhances insulin signaling via
suppression of protein tyrosine phosphatase 1B. J. Biol. Chem., 276:
39705-39712. PDF
Fan, G-f., Shumay, E., Wang, H-y., and Malbon, C.C. (2001) The Scaffold
Protein Gravin (AKAP250) binds the Beta2-adrenergic Receptor Via the Receptor
Cytoplasmic R329 to L413 Domain and Provides a Mobile Scaffold During
Desensitization. J. Biol. Chem., 276: 24005-24014. PDF
Liu, T., DeCostanzo, A. J., Liu, X., Wang, H-y., Hallagan,
S., Moon, R.T. and Malbon, C.C. (2001) Heterotrimeric
G-proteins Go and Gq mediate signaling from activation of rat Frizzled-1 to the
beta-catenin/Lef-Tcf pathway in development. Science, 292: 1718-1722.
PDF
Fan, F., Shumay, E., Malbon, C. C. and Wang, H-y. (2001) c-Src tyrosine
kinase binds the beta2-adrenergic receptor
via phospho-Tyr350, phosphorylates G-protein –linked Receptor Kinase 2, and
mediates agonist-induced receptor desensitization.J. Biol. Chem.,
276: 13240-13247. PDF
Wang, H-y., Doronin, S., and Malbon, C.C. (2000) Insulin Activation of
Mitogen-activated Protein Kinases Erk1,2 is Amplified via Beta-adrenergic
Receptor Expression and Requires the Integrity of the Tyr350 of the Receptor. J.
Biol. Chem., 275 (46):36086-36093. PDF
Kanungo, J., Potapova, I., Malbon, C. C., and Wang, H-y. (2000) Retinoic
Acid-induced Differentiation of P19 Embryonal Carcinoma Stem Cells is Mimicked
by Constitutively-active MEKK4 and MEKK1, but Blocked Only by the Dominant
Negative Mutant of MEKK4. J. Biol. Chem., 275, 24032-24039.
PDF
Lin, F., Wang, H-y. and Malbon, C.C. (2000) Gravin-mediated Formation of
Signaling Complexes in Beta2-Adrenergic Receptor Desensitization and Resensitization.
Biol.Chem.275,19025-19034. PDF
Kühl, M., Sheldahl, L., Malbon, C.C, and Moon, R.T. (2000) Ca2+/Calmodulin-dependent
Protein Kinase II is Stimulated by Wnt and Frizzled Homologs and Promotes
Ventral Cell Fates in Xenopus. J. Biol. Chem, 275,
12701-12711. PDF
Liu, X., Liu, T., Slusarski, D.C., Yang-Snyder, J., Malbon, C.C., Moon, R.T.,
and Wang, H-y. (1999) Activation of a Frizzled-2/beta-Adrenergic
Receptor Chimera promotes Wnt-Signaling and Differentiation of Mouse F9
Teratocarcinoma Cells via Galphao and Galphat. Proc. Natl. Acad. Sci. U.S.A., 96,
14383-14388. PDF
Morris, A.J. and Malbon, C.C. (1999) Physiological Regulation of
G-Protein-Mediated Signaling. Physiological Reviews. 79,
1373-1430 PDF
Shih, M., Lin, F. Scott, J.D., Wang, H-y. and Malbon, C.C.
(1999) Dynamic Complexation of b2-adrenergic receptors with Protein
Kinases and Phosphatases. J. Biol. Chem., 274, 1588-1595
PDF
Sheldahl, L., Park, M., Malbon, C.C. and Moon, R. (1999) Protein Kinase C is
Differentially Stimulated by Wnt and Frizzled Homologs in a G Protein Dependent Manner. Current Biology, 9: 695-698. PDF
Liu, X., Malbon, C.C., and Wang, H-y. (1998) Identification of Amino Acid
Residues of Gsalpha Critical to Repression of Adipogenesis. J. Biol
Chem. 273, 11685-11694. PDF
Guo, Jh., Wang, H-y., and Malbon, C.C. (1998) Conditional, Tissue-specific
Expression of Q205L Galphai2 in vivo Mimics Insulin Activation
of jun N-Terminal Kinase and P38 Kinase. J. Biol. Chem. 273,
16487-16493. PDF
Malbon, C.C. and Karoor, V. (1998) G-Protein-linked Receptors as Tyrosine
Kinase Substrates: News Paradigms in signal Integration. Cell
Signalling 8, 523-527. PDF
Shih, M and Malbon, C.C. (1998) Serum and Insulin-induced Grb2-dependents
Shift in Agonist Affinity for beta-adrenergic Receptor. Cell Signalling 8, 575-582. PDF
Zheng, X., Guo, Jh., Wang, H-y. and Malbon, C.C. (1998) Expression of Q205L
Galphai2 in vivo Ameliorates Streptozotocin-induced Diabetes. J. Biol. Chem.
273, 23649-23651. PDF
Karoor, V., Wang, L., Wang, H-y. and Malbon, C.C. (1998) Insulin
stimulates sequestration of beta-adrenergic receptor and enhanced association
of beta-adrenergic receptors with Grb2 via tyrosine 350. J. Biol. Chem., 273,
33035-3304. PDF
For further references, please see http://www.ncbi.nlm.nih.gov/PubMed/
Earlier Publications (selected)
Karoor, V. and Malbon, C.C. (1996)
IGF-1 stimulates phosphorylation of the beta 2-adrenergic receptor in
vivo on sites distinct from those phosphorylated in response to
insulin. J. Biol. Chem. 271,
29347-29352. PDF
Hockerman, G.H., Girvin, M.E., Malbon, C.C.
and Ruoho, A.E. (1996) Antagonist Conformations Within the
Beta-Adrenergic Receptor Ligand Binding Pocket. Mol.
Pharmacol. 49, 1021-1032.
Moxham, C.M., and Malbon, C.C. (1996) Gialpha2-deficiency
Impairs Insulin Action in vivo. Nature 379,
840-844.
Baltensperger, K., Karoor, V., Paul, H.,
Czech, M.P., Ruoho, A., and Malbon, C.C. (1996) The -Adrenergic
Receptor is a Substrate for the Insulin Receptor Kinase. J. Biol. Chem.
271, 1061-1064.
Moxham, C.M., Hod, Y., and Malbon, C.C.
(1993) Induction of Gialpha2-specific Antisense RNA in vivo
Inhibits Neonatal Growth. Science 260, 991-995.
Watkins, D.C., Johnson, G.L., and Malbon,
C.C. (1992) Regulation of the Differentiation of Teratocarcinoma Cells into
Primitive Endoderm by Gialpha2. Science 258,
1373-1375.
Wang, H.-y., Watkins, D.C., and Malbon, C.C.
(1992) Antisense Oligodeoxynucleotides to Gs Protein alpha-subunit
Sequence Accelerate Differentiation of Fibroblasts to Adipocytes. Nature 358,
334-337.
United State Patents
Patent Number: 5,858,774
Date of Patent: January 12, 1999
Antisense DNA Constructs for Expression of Hybrid MRNAS Driven by Inducible, Tissue-Specific Promoters.
Inventors: Craig C. Malbon, Christopher M. Moxham
Patent Number: 6,133,245
Date of Patent: October 17, 2000
Antisense DNA Constructs for Expression of Hybrid MRNAS Driven by Inducible, Tissue-Specific Promoters.
Inventors: Craig C. Malbon, Christopher M. Moxham
Patent Number: 6,007,991
Date of Patent: December 28, 1999
Antisense Oligonucleotides for Mitogen-Activated Protein Kinases as Therapy for Cancer
Intentors: Vimala S. Sivaraman, Hsien-yu Wang, Craig C. Malbon.
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