Faculty / Research

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 a research laboratory (1978- pres.) and the National Institutes of Health (NIDDK)-funded Diabetes & Metabolic Diseases Research Program (1986-pres). Prior to coming to Stony Brook, Dr. Malbon was trained at Case Western Reserve University, Brown University, and the Biological Laboratories at Harvard University. He is the 1997 recipient of the American Cancer Society Research Award, is an Honorary Member of The Biochemical Society (U.K.), and in 2004 Dr. Malbon received the American Cancer Society Award (Top 10 Researchers 1990-2000). Malbon was the recipient of the 2008 Goodman & Gilman Award from the American Society of Pharmacology & Experimental Therapeutics and was elected to the rank of fellow, AAAS that same year. As a theologian, he was appointed as a Visiting Scholar at Princeton Theological Seminary (Princeton, NJ), received his M. Div. from Union Theological Seminary in the City of New York (focused in Ethics), and performed chaplaincy training in the Catholic Healthcare Services of Long Island. His theological interests are in ethics, life, and society in 21st C America, with particular interest focused on end-of-life issues, right-to-die, and application of the moral theories of Immanuel Kant and Dietrich Bonhoeffer.

Link to Center of Medical Humanities:

http://www.stonybrook.edu/bioethics/malbon.shtml

Recent Publications (selected from 270+ publications, since 2005)

273.    Malbon, C. C. and Wang, H.Y. (2013)

            Isolation and Interrogation of Supermolecular Signalsome Complexes by Steric-

            exclusion Chromatography.

            (in "Transmembrane Signaling Protocols” of Methods in Molecular Biology

            Humana/Springer Publishers)

            1: 000-000, in the press

272.     Malbon, C.C. (2013) Library of Congress United States Copy Right Office 2012

            Abortion in 21^st Century America (Book)

            CreateSpace Independent Publishers (North Carolina), pp 266

271.     Bikkavilli, R.K., Avasarala, S., Vanscoyk, M., Scheler, M., Kelley, N.,

             Malbon, C.C., and Winn, R.A. (2012)

             Dishevelled3 is a Novel Arginine Methyl Transferase Substrate.

             Scientific Reports (Nature) 2: 805-811.

270.     Bikkavilli, R.K., and Malbon, C.C. (2012)

            Wnt3a-stimulated Arginine Methylation & LRP6 Phosphorylation.

            J. Cell Sci., 125:2446-2456.

269.     Kocer, S., Wang, H.Y., and Malbon, C.C. (2012)

             “Shaping” of Cell Signaling via AKAP-tethered PDE4D: Probing with AKAR2-AKAP5 Biosensor.

             J. Mol. Signaling, 7: 4-15. [See editorial commentary on article in Current Biology.]

268.     Yokoyama, N., Markova, N.G., Wang, H.Y., and Malbon, C.C. (2012)

            Assembly of Dishevelled 3-based Supermolecular Complexes via

            Phosphorylation and Axin.

            J. Mol. Signaling, 7: 8-26.

267.     Wang, H.-Y., and Malbon, C.C. (2012)

            Dishevelled C-terminus: Structural Insights.

            Acta Physiolog., 196: 65-73.

266.    Goa, S., Wang, H.-y., and Malbon, C. C. (2011)

            AKAP5 and AKAP12 Form Higher-Order Hetero-oligomers

            J. Mol. Signaling 6: 8-20.

265.    Goa, S., Wang, H.-y., and Malbon, C. C. (2011)

            AKAP5 and AKAP12 Form Homo-oligomers

            J. Mol. Signaling 6: 3-13.

264.    Bikkavilli, R.K., and Malbon, C. C. (2011)

            Arginine Methylation of G3BP1 by Wnt3a Regulates b-catenin mRNA.

            J. Cell Sci.124: 2310-2320.

263.    Wang, H.-y., and Malbon, C. C. (2011)

            Dishevelled C-terminus: Structural Insights

            Acta Physiolog. 195: 1748-1754.

262.    Malbon, C. C. (2011)

            Wnt Signaling: The Case of the “Missing” G Protein

            Biochem. J. 433: 3-6.

261.    Wang, H. -y., and Malbon, C. C. (2011)

            Probing the Physical Nature and Composition of Signalsomes

            J. Mol. Signal. 6: 1-10.

260.    Ma, L., Wang, Y., Malbon, C. C., and Wang, H.-y. (2010)

            Dishevelled-3 C-terminal His Single Amino Acid Repeats are Obligate for Wnt5a Activation of

            Non-canonical Signaling

            J. Mol. Signal. 5: 19-29.

259.    Yokoyama, N., Golebiewska, U., Wang, H.-y., and Malbon, C. C. (2010)

            Wnt-dependent Assembly of Supermolecular Dishevelled 3-based Complexes

            J. Cell Science 123: 3693-3702. (see “In This Issue” for highlights)

258.    Tao, J., Wang, H.-y., and Malbon, C. C. (2010)

            AKAR2-AKAP12 Fusion Protein “Biosenses” Dynamic Phosphorylation and Localization of a GPCR-based

            Scaffold

            J. Mol. Signaling 5: 17-39.

257.    Bikkavilli, R.K., and Malbon, C. C. (2010)

            Dishevelled-KSRP Complex Regulates Wnt Signaling through Post-transcriptional Stabilization of Beta-catenin 

            mRNA

            J. Cell Science 123: 1352-1362.

256.    Yokoyama, N., and Malbon, C. C. (2009)

            Dishevelled-2 Docks and Activates Src in a Wnt-dependent Manner.

            J. Cell Science 122: 4439-4451.

255.    Bikkavilli R.K., and Malbon, C. C. (2009)

            Mitogen-activated Protein Kinases and Wnt/b-Catenin Signaling: Molecular Conversations among Signaling

            Pathways

            Commun Integr Biol. 2:46-49.

254.    Chen, M.-h., and Malbon, C. C. (2009)

            G-protein-coupled Receptor-Associated A-kinase Anchoring Proteins AKAP5 and AKAP12: Differential Trafficking

            and Distribution.

            Cell Signal. 21:136-142.

253.    Tao, J., and Malbon, C. C. (2008)

            b-Adrenergic Receptor Recycling is Catalyzed by AKAP12, not AKAP5

            J. Mol. Signal. 3: 329-339.

252.    Bikkavilli, R.K., Feigin, M. E., and Malbon, C. C. (2008)

            p38 Mitogen-activated Protein Kinase Regulates Canonical Wnt/b-catenin Signaling by Inactivation of GSK3b

            J. Cell Science 121: 3598-3607.

251.    Okoye, U.C., Malbon, C. C., and Wang, H.-y. (2008)

            Wnt and Frizzled RNA Expression in Human Mesenchymal and Embryonic (H7)

            Stem Cells (PubMed “highly accessed article”)

            J. Mol. Signal. 3:16-22.

250.    Ma, Y., Malbon, C. C., Williams, D.L., and Thorngate, F. (2008)

            Aortic Lesions and Altered Gene Expression of Early Stage Atherosclerosis are Blocked by Low Levels of ApoE

            PLoS, 3: 2503-2512.

249.    Feigin, M. E., and Malbon, C. C. (2008)

            OSTM1 Regulates Beta-catenin/Lef1 Interaction and is Required for Wnt/beta-catenin Signaling

            Cell Signal. 20: 949-958.

248.    Bikkavilli, R.K., Feigin, M. E., and Malbon, C. C. (2008)

            G-protein Galpha o Mediates Wnt/c-Jun N-terminal Kinase Signaling through Dvl1,3/RhoA Family    

            Members/MEKK1,4 in Mammalian Cells

            J. Cell Science 121: 234-245.

247.    Yokoyama, N., and Malbon, C. C. (2007)

            Phosphoprotein Phosphatase 2A Docks to Dishevelled and Counterregulates Wnt3a/beta-catenin Signaling

            J. Mol. Signal. 2: 2-20.

246.    Yokoyama, N., and Malbon, C. C. (2007)

            Abundance, Complexation, and Trafficking of Wnt/beta-catenin Signaling Elements in Response to Wnt3a

            J. Mol. Signal. 2: 11-27.

245.    Feigin, M., and Malbon, C. C. (2007)

            RGS19 Regulation Wnt/b-catenin Signaling through Inactivation of Gao.

            J. Cell Science 120: 3404-3414.

244.    Malbon, C. C. (2007)

            A-Kinase Anchoring Proteins: Trafficking in G-protein-coupled Receptors and the Proteins that Regulate

            Receptor Biology

            Curr. Opin. Drug Discov. Devel. 10: 573-579.

243.    Shumay, E., Tao, J., Wang, H.-y., and Malbon, C. C. (2007)

            Lysophosphatidic Acid Regulates Trafficking of Beta-adrenergic Receptors: the Ga13/p115RhoGEF/JNK       

            Pathway Stimulates Receptor Internalization

            J. Biol. Chem. 282: 21529-21541.

242.    Gavi, S., Yin, D., Shumay, E., Wang, H.-y., and Malbon, C. C. (2007)

             IGF-1 Provokes Functional Antagonism and Internalization of Beta1-Adrenergic Receptors

             Endocrinology 148: 2653-2662.

241.    Yin, D., Gavi, S., Shumay, E., Wang, H.-y., and Malbon, C. C. (2006)

            Yeast Ste2 Receptors as Tools for Study of Mammalian Protein Kinases and Adaptors Involved in Receptor    

            Trafficking

            J. Molecular Signaling, 1: 2-8.

240.    Tao, J., Shumay, E., Wang, H.-y., and Malbon, C. C. (2007)

            Src Docks to A-kinase Anchoring Protein Gravin, Regulating Beta2-adrenergic Receptor Resensitization and

            Recycling

            J. Biol. Chem. 282: 6597-6608.

239.    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.

238.    Malbon, C. C., and Wang, H.-y. (2006)

            Dishevelled: A Mobile Scaffold Catalyzing Development

            Current Topics in Developmental Biology, 72: 153-178.

237.    Wang, H.-y., Liu, T., and Malbon, C. C.  (2006)

            Structure-Function Analysis of Frizzleds

            Cellular Signalling 18: 934-941.

236.    Wang, H.-y., Tao, J., Shumay, E., and Malbon, C. C. (2006)

            G protein-coupled Receptor-Associated A-kinase Anchoring Proteins: AKAP79 and AKAP250 (gravin)

            Eur. J. Cell Biology 85: 643-650.

235.    Gavi, S., Shumay, E., Wang, H.-y., and Malbon, C. C. (2006)

            G protein Coupled Receptors and Tyrosine Kinases: Crossroads in Cell Signaling and Regulation

            Trends in Endocrinology & Metabolism 17: 48-55.

234.    Yin, D., Gavi, S., Shumay, E., Duell, K., Konopka, J.B., Malbon, C. C., and Wang, H.-y. (2005)

            Successful Expression of a Functional Yeast G-protein-coupled receptor (Ste2) in Mammalian Cells

            Biochem. Biophys. Res. Commun. 329: 281-287.

233.    Gavi, S., Yin, D., Shumay, E., Malbon, C. C., and Wang, H.-y. (2005)

            The 15-Amino Acid Motif of the C Terminus of the ß₂-Adrenergic Receptor Is Sufficient to Confer Insulin-

            Stimulated Counterregulation to the ß₁-Adrenergic Receptor

            Endocrinology 146: 450-457.

232.    Malbon, C.C. (2005)

            Beta-Catenin, Cancer, and G Proteins: Not just for Frizzleds Anymore

            Science (STKE) 292, pe35.

231.    Malbon, C. C. (2005)

            G proteins in Development

            Nature Reviews: (Molecular Cell Biology), 6: 689-701.

230.    Malbon, C. C. and Wang, H.-y (2005)

            AKAP-based Scaffolds and Insulin Action

            Cell Science Rev. 12: 1742-1749.

The laboratory has trained more than 75 doctoral students, postdoctoral fellows, and research scientists, primarily in the area of cell signaling. In addition, the NIH-funded NIDDK Institutional Postdoctoral National Research Service Award (NRSA) Program directed by Dr. Malbon has trained nearly 100 fellows, both the clinically-trained (M.D.) and basic sciences-trained (Ph.D., D.Sc.), in its 25 year history of continuous support. Links to lists of both Malbon laboratory alumni and of DMDRC NRSA alumni (selective, not exhaustive) are provided below.

MALBON LABORATORY

Department of Pharmacology
Diabetes and Metabolic Diseases Research Center

School of Medicine
SUNY at Stony Brook, HSC-BST T7, Rm 156,
Stony Brook NY 11794-8651

Tel:631-444-7873 Fax:631-444-7696
e-mail: craig@pharm.sunysb.edu

Malbon Laboratory Research

REGULATION OF HORMONE-SENSITIVE EFFECTOR SYSTEMS

The role of heterotrimeric G proteins in the signaling of Wnts has been established, from flies to mammals. Wnts signal, in part, via heptahelical G protein coupled receptors (GPCR) to effectors systems that control fundamental processes, such as adipogenesis, bone formation, cell progression, cell fate, and other aspects of early development. Dysregulation of Wnt signaling provides a basis for human disease, including cancer. The phosphoprotein Dishevelled (DVD) is essential to Wnt/b-

catenin (canonical), Wnt/ca²⁺/cGMP, and Wnt/planar cell polarity (PCP) pathways. Wnts promote mouse F9 embryonic teratocarcinoma cells (F9) to primitive endoderm (PE) and each of these effector pathways, via one/more or 3 mammalian Dvls. We propose 3 specific aims: (i) to define functional roles of mammalian Dvls on each major Wnt-stimulated pathway using siRNA and read outs of b-catenin stability, Lef/Tcf-sensitive transcription, Ca²⁺ imaging and cGMP analysis, JNK activation via Rho, and PE formation; (ii) to establish multivalency of Dvl interactions with GPCR, G proteins, kinases/phosphatases, and adaptor molecules critical to Wnt signaling making use of tandem affinity-based purification (TAP) and advanced

proteomics (MALDI, QToF, and nanospray mass spectrometry), siRNA-based knock downs, enzyme inhibitors/dominant negative constructs, and eventual mutagenesis of potential docking sites; and (iii) to establish the functional consequences of spatial localization and trafficking of Dvl in naïve and Wnt-activated F9 cells, focusing on defining the dynamic aspects of activation /deactivation using fluorescence-based strategies (including e photon, fcs, and TIRF microscopy), energy transfer measurements in live cells (via BRET), and cell fractionation coupled with TAP-tagged Dvl followed by proteomics. The overarching hypothesis is that Dvls function as dynamic scaffolds for integration of cell signaling to a spectrum of diverse pathways, much like the AKAP protein family members function. Dvls both dock and are candidate substrates for many kinases/phosphatases, although the details of these interactive regulations remain to be established by proteomics. Real-time measurements of docking in live cells are made possible by BRET and parallel biochemical/proteomics assays that can define the status of Dvl with respect to protein phosphorylation. The functional basis for 3 mammalian Dvls, for their spatial and temporal trafficking, and for cell membrane association are addressed using in vivo and in vitro strategies. Understanding the multivalency and docking of Dvl open opportunity to intervene in the primary signaling pathways controlled by Wnts, including those whose dysregulation leads to cancer, birth defects, and altered bone formation. Dvls, as multivalent dynamic scaffolds, are high-value likely targets for new therapies.

STRUCTURE AND BIOLOGY OF BETA –ADRENERGIC RECEPTORS
 

A-Kinase Anchoring Proteins constitute a diverse family of scaffold proteins which share a common binding site for the RI/II subunit of PKA and are now recognized as scaffolds for multivalent cell signaling. AKAP250 (a.k.a., AKAP12, gravin, or a human homologue of SSeCKS) plays a critical role in signaling of the b2-adrenergic receptor (b2AR), the prototype for the superfamily of G-protein-coupled receptors (GPCR). We have demonstrated that AKAP250 is multivalent, providing a scaffold for b2AR signaling complexes that include minimally PKA, PKC, PP2B, Src, and the b2AR. Agonist activation of the b2AR stimulates eventual desensitization, sequestration, resensitization, and recycling of the receptor, a process disrupted in the absence of AKAP250. Recently we have mapped the domains of the b2AR as well as those for AKAP250 that provide the basis for protein-protein interactions

and a central role of protein phosphorylation in defining this dynamic interaction. The overarching goal of this research plan is to understand at the “meso”-scale, the dynamic role of AKAP scaffold in b2AR signaling complexes. Four specific aims target the goal: namely 1) to probe protein-lipid and protein-protein interactions of AKAP250 in b2AR signaling (focusing on three domains that may dictate scaffold-membrane association); 2) to identify new signaling molecules that constitute AKAP-based b2AR signaling complexes and to establish their function in the complex (making use of yeast-2-hybrid and HTS proteomic analysis of complex pull-downs); 3) to map the spatial organization and trafficking mechanisms of b2AR signaling complexes in response to stimulation by b-agonist (desensitization) and by insulin (counterregulation), using 2-photon confocal and bioluminescence resonance energy transfer (BRET) spectroscopy; and 4) to elucidate the ordered pattern of phosphorylation of key molecules constituting

AKAP-based b2AR signaling complexes and its function in the dynamic regulation of the complexes (using mass spectrometry in tandem with domain-specific mutagenesis). The targeted convergence of mass spectrometry-based proteomics, sensitive multi-photon confocal microscopy, BRET, and read-outs of localization, function, and protein-protein interactions create an unparalleled opportunity for success.

Atherosclerosis and Peripheral Apoprotein E Synthesis

The long term objective of this research is to understand the functional basis for the expression of lipoprotein (apo) E in peripheral tissues. ApoE is important for regulating systemic cholesterol transport metabolism. Among the plasma apolipoproteins, apoE is unusual in being expressed in many tissues and is involved in cellular processes and diseases that are independent of systemic lipoprotein metabolism. This proposal has two primary objectives. The first is to define the mechanisms by which low-levels of plasma apoE suppress atherosclerotic lesion development. Previous studies showed that

levels of transgenic apoE too low to correct hypercholesterolemia in apoE-deficient mice still blocked aortic lesion formation. The second goal is to determine how localized apoE expression in adrenocortical cells regulates the utilization of cholesterol for steroid production. These studies employ apoE-deficient mouse lines that have been engineered to express different levels of transgenic apoE selectively in the adrenal gland. The proposal has 3 aims. Aim 1 has 3 goals focused on how low-levels

(= 10^-8M) of apoE alter the initial stages of lesion formation. Goal 1 will use quantitative real-time PCR to monitor expression of a set of candidate genes during initial stages of leukocyte recruitment to the vascular wall. Goal 2 will determine whether signaling pathways for platelet derived growth factor (PDGF) or those involving the transcription the transcription factors NF-aB and Egr-1 are activated in vascular cells at early stages, and whether low-level apoE alters this activation. Goal 3 will test which receptors of the LDL receptor family are important for the atheroprotective effects of low-level apoE. Airm 2 will use transgenic mice expressing apoE in adrenocortical cells to define mechanisms by which apoE alters cholesterol utilization. Goal 1 will use immunocytochemical approaches to evaluate the variegated pattern of transgenic apoE expression in the adrenal cortex and to test the effect of localized apoE on the expression of key proteins involved in the provision of substrate cholesterol to the steroidogenic pathway. Goal 2 will test which receptors of the LDL receptor family are important for the effects of apoE in adrenocortical cells. Aim 3 has collaborative projects to test the effects of low-level apoE. On neointimal formation after arterial injury and on regression of atherosclerotic lesions. These studies will provide new mechanistic formation about actions of apoE on cholesterol and metabolism and atherosclerosis.

Laboratory Staff

Postdoctoral Research Training Program

National Institutes of Health, National Research Service Award

The institutional NRSA program sponsored by the Diabetes & Metabolic Diseases Research Center (DMDRC) offers multidisciplinary post-graduate training opportunities to the scientifically-trained (Ph.D.) and clinically-trained (M.D.) to acquire expertise in the study of metabolic diseases using state-of-the-art approaches of biochemistry, cell and molecular biology. Opportunities for training include diabetes & insulin action, protein metabolism, G-protein-coupled receptor action in disease states, cell signaling, Ras and MAP kinase regulation. Expertise is derived from 27 trainers from 9 departments with basic/clinical research in 5 major disciplines (physiology, pharmacology, biochemistry, molecular biology & cell biology). The training faculty support the tenet that a successful research career in the diverse and multifaceted area of endocrine and metabolic diseases requires a broadly-based background founded in these five major disciplines as well as a hybrid perspective which is receptive to strategies transcending the limits of one's immediate specialty. Training is principally as participants in vigorous, supportive research programs of individual trainers as well as more-broadly-based training as DMDRC members. Trainees actively participate in weekly interdepartmental seminars, minisymposia, journal clubs in specialized areas (endocrinology, cell signaling), and periodic scientific meetings where reports on original research are presented. The trainees (8 per year) will be principally medical (M.D.) or Ph.D. graduates who demonstrate a keen interest in taking advantage of these opportunities. Emphasis is placed on the vigorous recruitment of women and underrepresented minorities. Trainees are selected based upon their ability to conduct original research in a careful and critical manner, the nature and quality of their thesis and/or prior work, and recommendations by referees. Competitive applicants visit the campus and present a seminar. Facilities include modern laboratories (>80,000 n.s.f.) equipped for original research endeavors. Unique opportunities exist for advanced training in transgenic and KO mice use, molecular biology, proteomics (MALDI and QToF mass spectrometry) & structural biology, microscopy & imaging analysis, DNA microarray, and iRNA use. The DMDRC T32 program sponsors bioethics training, career building, and planning. The DMDRC training program enjoys strong University-wide support.


Transgenic mouse models of human G-protein-based disease

Organization

Trainees

TO VIEW MALBON LABORATORY TRAINEES (1976-2010) CLICK HERE

DMDRC office, Ms. Rexa Whitley (voice phone + voice mail)            631-444-3078;

CCM office (voice phone + voice mail)                                                631-444-3077;

Laboratory voice phone                                                                       631-444-3639;

Email address:                                                             craig@pharm.stonybrook.edu