Adriano Marchese
  • Associate Professor
  • Molecular Pharmacology and Therapeutics
Research Keywords
  • Bioenergetics
  • Cancer/Carcinogenesis
  • Receptors
  • Signal Transduction
Research Summary

Research in the Marchese lab is directed towards understanding the molecular mechanisms governing G protein-coupled receptor (GPCR) signaling. GPCRs are cell surface receptors expressed throughout the body, mediating a variety of physiological processes such as smell, taste, vision, neurotransmission, cardiovascular control, chemotaxis, pain tolerance, immunity and much more. GPCRs are also targets, either directly or indirectly, for a large fraction of prescribed medicines sold worldwide to treat a variety of diseases. Our goal is to elucidate the mechanisms governing GPCR signaling with the objective of gaining a better understanding of how GPCR signaling contributes to disease and with the hope of identifying novel therapeutic targets that could be used to develop new medicines with less side effects.

Our work is focused primarily on the chemokine receptor CXCR4, a prototypical GPCR implicated in several diseases, and of particular interest to us is the role that it plays in cancer progression. CXCR4 is over-expressed on the surface of many types of cancer cells and its expression correlates with poor prognosis. CXCR4 expressing cancer cells tend to colonize distant anatomical sites where the cognate ligand for CXCR4 called CXCL12 is located, such as liver, bone marrow, lungs and lymph nodes, leading to metastatic disease. Most cancer related deaths are due to metastasis. Although targeting CXCR4 directly with small molecule antagonists has proven to be effective at reducing metastatic disease in preclinical animal models, this strategy has limited clinical benefit due to untoward side effects. Identifying the downstream signaling pathways responsible for promoting CXCR4-dependent metastatic disease could lead to identifying novel targets that could potentially be affected by drugs without side effects.

Current efforts in the Marchese lab are focused on two major areas. In one area we are focused on elucidating the molecular mechanisms regulating CXCR4 expression in cells. In particular we are studying how CXCR4 levels are regulated by membrane trafficking within the endocytic pathway. Under normal circumstances, upon binding to its ligand CXCL12 at the cell surface, CXCR4 is rapidly internalized and trafficked along the endocytic pathway to lysosomes where it is degraded. We hope to better understand how CXCR4 is trafficked to lysosomes and degraded and to establish whether this is defective in cancer cells in which CXCR4 is over-expressed. In another area of research, we are focused on understanding the pathways that are involved in promoting CXCR4-induced cell migration. The role that CXCR4 plays in metastatic disease is linked to its ability to promote migration of cancer cells from the primary tumor site towards a gradient of its ligand CXCL12 to reach secondary organs. We hope to better understand the signaling pathways responsible for promoting CXCR4-mediated migration with the goal of developing novel therapeutic strategies to prevent metastatic disease that depends on CXCR4.


The Endosomal Sorting Complex Required for Transport Pathway Mediates Chemokine Receptor CXCR4-promoted Lysosomal Degradation of the Mammalian Target of Rapamycin Antagonist DEPTORVerma,R.; Marchese,A.The Journal of biological chemistry 2015 ;290(11):6810-6824

Endocytic trafficking of chemokine receptorsMarchese,A.Current opinion in cell biology 2014 ;27C( ):72-77

The ubiquitin ligase Deltex-3L regulates endosomal sorting of the G protein-coupled receptor CXCR4Holleman,J.; Marchese,A.Molecular biology of the cell 2014 ; ( ):

Modulation of the CXC Chemokine Receptor 4 Agonist Activity of Ubiquitin through C-Terminal Protein ModificationTripathi,A.; Saini,V.; Marchese,A.; Volkman,B. F.; Tang,W. J.; Majetschak,M.Biochemistry 2013 ; ( ):

Ubiquitin-dependent regulation of G protein-coupled receptor trafficking and signalingMarchese,A.; Trejo,J.Cellular signalling 2013 ;25(3):707-716

Novel roles for the E3 ubiquitin ligase atrophin-interacting protein 4 and signal transduction adaptor molecule 1 in G protein-coupled receptor signaling.Malik,R.; Soh,U. J.; Trejo,J.; Marchese,A.Journal of Biological Chemistry 2012 ;287(12):9013-9027

AP-3 regulates PAR1 ubiquitin-independent MVB/lysosomal sorting via an ALIX-mediated pathwayDores,M. R.; Paing,M. M.; Lin,H.; Montagne,W. A.; Marchese,A.; Trejo,J.Molecular biology of the cell 2012 ;23(18):3612-3623

The CXC chemokine receptor 4 ligands ubiquitin and stromal cell-derived factor-1alpha function through distinct receptor interactions.Saini,V.; Staren,D. M.; Ziarek,J. J.; Nashaat,Z. N.; Campbell,E. M.; Volkman,B. F.; Marchese,A.; Majetschak,M.Journal of Biological Chemistry 2011 ;286(38):33466-33477

Structural determinants of ubiquitin-CXC chemokine receptor 4 interactionSaini,V.; Marchese,A.; Tang,W. J.; Majetschak,M.The Journal of biological chemistry 2011 ;286(51):44145-44152

Small ubiquitin-like modifier modification of arrestin-3 regulates receptor trafficking.Wyatt,D.; Malik,R.; Vesecky,A. C.; Marchese,A.Journal of Biological Chemistry 2011 ;286(5):3884-3893

Ubiquitination of GPCRs.Caballero,A.; Marchese,A.Methods in Molecular Biology 2011 ;746( ):251-259

Arrestin-2 interacts with the endosomal sorting complex required for transport machinery to modulate endosomal sorting of CXCR4.Malik,R.; Marchese,A.Molecular biology of the cell 2010 ;21(14):2529-2541

CXC chemokine receptor 4 is a cell surface receptor for extracellular ubiquitin.Saini,V.; Marchese,A.; Majetschak,M.Journal of Biological Chemistry 2010 ;285(20):15566-15576

Ubiquitin receptor binding and signaling in primary human leukocytesSaini,V.; Romero,J.; Marchese,A.; Majetschak,M.Communicative & integrative biology 2010 ;3(6):608-610

Ubiquitination regulates proteolytic processing of G protein-coupled receptors after their sorting to lysosomesHislop,J. N.; Henry,A. G.; Marchese,A.; von Zastrow,M.The Journal of biological chemistry 2009 ;284(29):19361-19370

The E3 ubiquitin ligase atrophin interacting protein 4 binds directly to the chemokine receptor CXCR4 via a novel WW domain-mediated interaction.Bhandari,D.; Robia,S. L.; Marchese,A.Molecular biology of the cell 2009 ;20(5):1324-1339

Ubiquitination of chemokine receptors.Marchese,A.Methods in enzymology 2009 ;460( ):413-422

Cross-talk between notch and the estrogen receptor in breast cancer suggests novel therapeutic approachesRizzo,P.; Miao,H.; D'Souza,G.; Osipo,C.; Song,L. L.; Yun,J.; Zhao,H.; Mascarenhas,J.; Wyatt,D.; Antico,G.; Hao,L.; Yao,K.; Rajan,P.; Hicks,C.; Siziopikou,K.; Selvaggi,S.; Bashir,A.; Bhandari,D.; Marchese,A.; Lendahl,U.; Qin,J. Z.; Tonetti,D. A.; Albain,K.; Nickoloff,B. J.; Miele,L.Cancer research 2008 ;68(13):5226-5235

G protein-coupled receptor sorting to endosomes and lysosomesMarchese,A.; Paing,M. M.; Temple,B. R.; Trejo,J.Annual Review of Pharmacology and Toxicology 2008 ;48( ):601-629

Arrestin-2 interacts with the ubiquitin-protein isopeptide ligase atrophin-interacting protein 4 and mediates endosomal sorting of the chemokine receptor CXCR4.Bhandari,D.; Trejo,J.; Benovic,J. L.; Marchese,A.Journal of Biological Chemistry 2007 ;282(51):36971-36979

Ubiquitination differentially regulates clathrin-dependent internalization of protease-activated receptor-1.Wolfe,B. L.; Marchese,A.; Trejo,J.Journal of Cell Biology 2007 ;177(5):905-916

CISK attenuates degradation of the chemokine receptor CXCR4 via the ubiquitin ligase AIP4.Slagsvold,T.; Marchese,A.; Brech,A.; Stenmark,H.EMBO Journal 2006 ;25(16):3738-3749

Assessment of degradation and ubiquitination of CXCR4, a GPCR regulated by EGFR family members.Marchese,A.Methods in Molecular Biology 2006 ;327( ):139-145

Ubiquitination of G-protein-coupled receptorsMarchese,A.; Benovic,J. L.Methods in molecular biology (Clifton, N.J.) 2004 ;259( ):299-305

A new key in breast cancer metastasisBenovic,J. L.; Marchese,A.CANCER CELL 2004 ;6(5):429-430

The ins and outs of G protein-coupled receptor traffickingMarchese,A.; Chen,C.; Kim,Y. M.; Benovic,J. L.Trends in biochemical sciences 2003 ;28(7):369-376

The Grb10/Nedd4 complex regulates ligand-induced ubiquitination and stability of the insulin-like growth factor I receptorVecchione,A.; Marchese,A.; Henry,P.; Rotin,D.; Morrione,A.Molecular and cellular biology 2003 ;23(9):3363-3372

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