Adriano Marchese
  • Associate Professor
  • Molecular Pharmacology and Therapeutics
Research Summary

Regulation of receptor-mediated signal transduction in cancer and chronic pain

G protein-coupled receptors (GPCRs) mediate a wide range of physiological processes from controlling blood pressure, pain perception, vision, taste, among others. Dysregulation of GPCR signaling has been linked to several pathologies such as hypertension, several neuropyschiatric diseases, neuropathic pain and cancer among many more. Understanding how GPCRs are regulated may lead to a better understanding of the molecular mechanisms underlying the pathophysiology of diseases associated with GPCR dysregulation and may lead to the identification of novel therapeutic targets.

The molecular and cellular mechanisms regulating GPCRs are complex and are not completely understood. In general, upon activation by a stimulus many GPCRs are removed from the cell surface by a process known as endocytosis. Once inside the cell the receptor appears in an intracellular compartment known as an early endosome. Although a great deal is known about the mechanisms regulating internalization of GPCRs, the mechanisms regulating their fate once on early endosomes remains poorly understood. GPCRs can enter one of two pathways: (1) a recycling pathway, whereby GPCRs are recycled back to the plasma membrane, with the ability to respond again to stimulation, a process known as resensitization; or (2) a degradative pathway, whereby GPCRs are targeted to lysosomes for proteolysis resulting in long term attenuation of signaling, a process known as downregulation. The molecular mechanisms mediating sorting into one of these two pathways remains poorly understood and remains one of the key areas of research that we are currently addressing.

To address this we are focused on studying the chemokine receptor CXCR4. CXCR4 is an essential protein that is involved in important cellular processes such as development of the brain and heart, stem cell migration and leukocyte chemotaxis. CXCR4 also plays a critical role in the pathology of HIV via its role as an entry co-receptor and has been shown to have a role in neuropathic pain. In addition, CXCR4 has been implicated in cancer. It is found to be over-expressed in at least 23 different cancers, especially in breast cancer. In a subset of breast cancers, increased expression of CXCR4 on the surface of cancer cells appears to contribute to the metastatic potential of the cancer cells. The increased levels of CXCR4 have in part been linked to an inability of the receptor to be properly sorted for degradation, but the mechanistic details remain unknown. We believe that understanding how CXCR4 is regulated will further our knowledge of the molecular mechanisms underlying the pathophysiology of diseases associated with CXCR4 and may lead to the identification of novel therapeutic targets to treat pathologies such as cancer.

Therefore research in our laboratory is directed towards understanding the molecular mechanisms governing the regulation of CXCR4. We have previously shown that CXCR4 undergoes agonist-dependent ubiquitination by the E3 ubiquitin ligase AIP4, which serves to target the receptor to lysosomes where it is degraded. However, the molecular mechanisms by which AIP4 regulates CXCR4 ubiquitination and trafficking remain poorly understood. Therefore, we are specifically engaged in research that will provide mechanistic insight into the molecular processes that govern AIP4 regulation of CXCR4.


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

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

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

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 ; ( ):

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

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

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

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

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

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

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

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 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

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 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

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