Keywords
Last Name

Mikel Garcia-Marcos, PhD

TitleAssistant Professor
InstitutionBoston University School of Medicine
DepartmentBiochemistry
Address72 E. Concord Street
Boston MA 02118
Phone(617) 638-4047
Fax(617) 638-5339
ORCID ORCID Icon0000-0001-9513-4826
 Research Expertise & Professional Interests
Research Interests: G PROTEIN SIGNALING CIRCUITS IN THE MOLECULAR BASIS OF DISEASE.

A major goal of cell biology is to understand how cells respond to changes in their environment through a mechanism known as signal transduction. Dysregulation of this process is intimately related to the development of many diseases such as cancer, cardiovascular disease, inflammation, diabetes, etc. Our laboratory is interested in investigating how signaling via trimeric G proteins controls cell behavior in health and disease.

Trimeric G proteins are gate-keepers of signal transduction that regulate virtually any physiological process and dysregulation of their function is the cause of many diseases. The biomedical importance and impact in public health of this signaling mechanism is made most notorious by the fact that more than 25% of the marketed drugs target it. Although this is a well established signal transduction mechanism, recent discoveries have uncovered an increased complexity in the G protein regulatory network. It has become clear that in addition to G protein coupled receptors (GPCRs) other accessory proteins (e.g., GAPs and GDIs) also control G protein activity and function. These accessory proteins contribute to the assembly of alternative or complementary signaling circuits that shape cellular responses.

We have contributed to the characterization of a new type of “atypical” G protein regulators called non-receptor GEFs, which mimic the action exerted by GPCRs but are not membrane receptors. We recently demonstrated that GIV (a.k.a. Girdin) is the first non-receptor GEF that works via a defined motif and found that it controls cell migration, mitosis and autophagy. We also identified a critical role of GIV’s GEF function in the development of human disease as its abnormal upregulation in tumor cells promotes cancer metastasis, the cause of 95% of cancer-related deaths. Importantly, the survival rate for patients with GIV-positive tumors is dramatically reduced compared to the patients with GIV-negative tumors. Thus, GIV has emerged as novel G protein regulator with a critical role in cancer.

Our overall hypothesis is that GIV is the first member of a larger family of novel G protein regulators that control cellular behavior by virtue of coupling to G proteins via a signature GEF motif. We propose that the interplay between members of this new family of proteins and other components of the G protein regulatory machinery represents a new paradigm differing from the canonical view of trimeric G proteins and that dysregulation of this novel mechanism of signal transduction can give rise to different diseases. In addition, disruption of the GEF motif-G protein interface may be exploited as a therapeutic target in diseased states triggered by enhancement of the GEF function, as it occurs for GIV during cancer metastasis.

Our current goals can be summarized as follows:
1)To identify and characterize members of a new family of G protein regulators that share a common GEF motif.
2)To investigate how the interplay between these new regulators and other signaling proteins establishes non-canonical signaling circuits to control cell behavior.
3)To dissect the structural determinants required to assemble the GEF-G protein interface and to identify molecular probes for the therapeutic targeting of this interface.

 Publications
Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
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  1. Leyme A, Marivin A, Casler J, Nguyen LT, Garcia-Marcos M. Different biochemical properties explain why two equivalent ga subunit mutants cause unrelated diseases. J Biol Chem. 2014 Aug 8; 289(32):21818-27.
    View in: PubMed
  2. López-Sánchez I, Garcia-Marcos M, Mittal Y, Aznar N, Farquhar MG, Ghosh P. Protein kinase C-theta (PKC?) phosphorylates and inhibits the guanine exchange factor, GIV/Girdin. Proc Natl Acad Sci U S A. 2013 Apr 2; 110(14):5510-5.
    View in: PubMed
  3. Beas AO, Taupin V, Teodorof C, Nguyen LT, Garcia-Marcos M, Farquhar MG. Gas promotes EEA1 endosome maturation and shuts down proliferative signaling through interaction with GIV (Girdin). Mol Biol Cell. 2012 Dec; 23(23):4623-34.
    View in: PubMed
  4. Klionsky DJ, Abdalla FC, Abeliovich H, Abraham RT, Acevedo-Arozena A, Adeli K, Agholme L, Agnello M, Agostinis P, Aguirre-Ghiso JA, Ahn HJ, Ait-Mohamed O, Ait-Si-Ali S, Akematsu T, Akira S, Al-Younes HM, Al-Zeer MA, Albert ML, Albin RL, Alegre-Abarrategui J, Aleo MF, Alirezaei M, Almasan A, Almonte-Becerril M, Amano A, Amaravadi R, Amarnath S, Amer AO, Andrieu-Abadie N, Anantharam V, Ann DK, Anoopkumar-Dukie S, Aoki H, Apostolova N, Arancia G, Aris JP, Asanuma K, Asare NY, Ashida H, Askanas V, Askew DS, Auberger P, Baba M, Backues SK, Baehrecke EH, Bahr BA, Bai XY, Bailly Y, Baiocchi R, Baldini G, Balduini W, Ballabio A, Bamber BA, Bampton ET, Bánhegyi G, Bartholomew CR, Bassham DC, Bast RC, Batoko H, Bay BH, Beau I, Béchet DM, Begley TJ, Behl C, Behrends C, Bekri S, Bellaire B, Bendall LJ, Benetti L, Berliocchi L, Bernardi H, Bernassola F, Besteiro S, Bhatia-Kissova I, Bi X, Biard-Piechaczyk M, Blum JS, Boise LH, Bonaldo P, Boone DL, Bornhauser BC, Bortoluci KR, Bossis I, Bost F, Bourquin JP, Boya P, Boyer-Guittaut M, Bozhkov PV, Brady NR, Brancolini C, Brech A, Brenman JE, Brennand A, Bresnick EH, Brest P, Bridges D, Bristol ML, Brookes PS, Brown EJ, Brumell JH, Brunetti-Pierri N, Brunk UT, Bulman DE, Bultman SJ, Bultynck G, Burbulla LF, Bursch W, Butchar JP, Buzgariu W, Bydlowski SP, Cadwell K, Cahová M, Cai D, Cai J, Cai Q, Calabretta B, Calvo-Garrido J, Camougrand N, Campanella M, Campos-Salinas J, Candi E, Cao L, Caplan AB, Carding SR, Cardoso SM, Carew JS, Carlin CR, Carmignac V, Carneiro LA, Carra S, Caruso RA, Casari G, Casas C, Castino R, Cebollero E, Cecconi F, Celli J, Chaachouay H, Chae HJ, Chai CY, Chan DC, Chan EY, Chang RC, Che CM, Chen CC, Chen GC, Chen GQ, Chen M, Chen Q, Chen SS, Chen W, Chen X, Chen X, Chen X, Chen YG, Chen Y, Chen Y, Chen YJ, Chen Z, Cheng A, Cheng CH, Cheng Y, Cheong H, Cheong JH, Cherry S, Chess-Williams R, Cheung ZH, Chevet E, Chiang HL, Chiarelli R, Chiba T, Chin LS, Chiou SH, Chisari FV, Cho CH, Cho DH, Choi AM, Choi D, Choi KS, Choi ME, Chouaib S, Choubey D, Choubey V, Chu CT, Chuang TH, Chueh SH, Chun T, Chwae YJ, Chye ML, Ciarcia R, Ciriolo MR, Clague MJ, Clark RS, Clarke PG, Clarke R, Codogno P, Coller HA, Colombo MI, Comincini S, Condello M, Condorelli F, Cookson MR, Coombs GH, Coppens I, Corbalan R, Cossart P, Costelli P, Costes S, Coto-Montes A, Couve E, Coxon FP, Cregg JM, Crespo JL, Cronjé MJ, Cuervo AM, Cullen JJ, Czaja MJ, D'Amelio M, Darfeuille-Michaud A, Davids LM, Davies FE, De Felici M, de Groot JF, de Haan CA, De Martino L, De Milito A, De Tata V, Debnath J, Degterev A, Dehay B, Delbridge LM, Demarchi F, Deng YZ, Dengjel J, Dent P, Denton D, Deretic V, Desai SD, Devenish RJ, Di Gioacchino M, Di Paolo G, Di Pietro C, Díaz-Araya G, Díaz-Laviada I, Diaz-Meco MT, Diaz-Nido J, Dikic I, Dinesh-Kumar SP, Ding WX, Distelhorst CW, Diwan A, Djavaheri-Mergny M, Dokudovskaya S, Dong Z, Dorsey FC, Dosenko V, Dowling JJ, Doxsey S, Dreux M, Drew ME, Duan Q, Duchosal MA, Duff K, Dugail I, Durbeej M, Duszenko M, Edelstein CL, Edinger AL, Egea G, Eichinger L, Eissa NT, Ekmekcioglu S, El-Deiry WS, Elazar Z, Elgendy M, Ellerby LM, Eng KE, Engelbrecht AM, Engelender S, Erenpreisa J, Escalante R, Esclatine A, Eskelinen EL, Espert L, Espina V, Fan H, Fan J, Fan QW, Fan Z, Fang S, Fang Y, Fanto M, Fanzani A, Farkas T, Farré JC, Faure M, Fechheimer M, Feng CG, Feng J, Feng Q, Feng Y, Fésüs L, Feuer R, Figueiredo-Pereira ME, Fimia GM, Fingar DC, Finkbeiner S, Finkel T, Finley KD, Fiorito F, Fisher EA, Fisher PB, Flajolet M, Florez-McClure ML, Florio S, Fon EA, Fornai F, Fortunato F, Fotedar R, Fowler DH, Fox HS, Franco R, Frankel LB, Fransen M, Fuentes JM, Fueyo J, Fujii J, Fujisaki K, Fujita E, Fukuda M, Furukawa RH, Gaestel M, Gailly P, Gajewska M, Galliot B, Galy V, Ganesh S, Ganetzky B, Ganley IG, Gao FB, Gao GF, Gao J, Garcia L, Garcia-Manero G, Garcia-Marcos M, Garmyn M, Gartel AL, Gatti E, Gautel M, Gawriluk TR, Gegg ME, Geng J, Germain M, Gestwicki JE, Gewirtz DA, Ghavami S, et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy. 2012 Apr; 8(4):445-544.
    View in: PubMed
  5. Garcia-Marcos M, Kietrsunthorn PS, Pavlova Y, Adia MA, Ghosh P, Farquhar MG. Functional characterization of the guanine nucleotide exchange factor (GEF) motif of GIV protein reveals a threshold effect in signaling. Proc Natl Acad Sci U S A. 2012 Feb 7; 109(6):1961-6.
    View in: PubMed
  6. Lin C, Ear J, Pavlova Y, Mittal Y, Kufareva I, Ghassemian M, Abagyan R, Garcia-Marcos M, Ghosh P. Tyrosine phosphorylation of the Ga-interacting protein GIV promotes activation of phosphoinositide 3-kinase during cell migration. Sci Signal. 2011 Sep 27; 4(192):ra64.
    View in: PubMed
  7. Mittal Y, Pavlova Y, Garcia-Marcos M, Ghosh P. Src homology domain 2-containing protein-tyrosine phosphatase-1 (SHP-1) binds and dephosphorylates G(alpha)-interacting, vesicle-associated protein (GIV)/Girdin and attenuates the GIV-phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway. J Biol Chem. 2011 Sep 16; 286(37):32404-15.
    View in: PubMed
  8. Garcia-Marcos M, Kietrsunthorn PS, Wang H, Ghosh P, Farquhar MG. G Protein binding sites on Calnuc (nucleobindin 1) and NUCB2 (nucleobindin 2) define a new class of G(alpha)i-regulatory motifs. J Biol Chem. 2011 Aug 12; 286(32):28138-49.
    View in: PubMed
  9. Ghosh P, Garcia-Marcos M, Farquhar MG. GIV/Girdin is a rheostat that fine-tunes growth factor signals during tumor progression. Cell Adh Migr. 2011 May-Jun; 5(3):237-48.
    View in: PubMed
  10. Garcia-Marcos M, Ear J, Farquhar MG, Ghosh P. A GDI (AGS3) and a GEF (GIV) regulate autophagy by balancing G protein activity and growth factor signals. Mol Biol Cell. 2011 Mar 1; 22(5):673-86.
    View in: PubMed
  11. Garcia-Marcos M, Jung BH, Ear J, Cabrera B, Carethers JM, Ghosh P. Expression of GIV/Girdin, a metastasis-related protein, predicts patient survival in colon cancer. FASEB J. 2011 Feb; 25(2):590-9.
    View in: PubMed
  12. Ghosh P, Beas AO, Bornheimer SJ, Garcia-Marcos M, Forry EP, Johannson C, Ear J, Jung BH, Cabrera B, Carethers JM, Farquhar MG. A G{alpha}i-GIV molecular complex binds epidermal growth factor receptor and determines whether cells migrate or proliferate. Mol Biol Cell. 2010 Jul 1; 21(13):2338-54.
    View in: PubMed
  13. Garcia-Marcos M, Ghosh P, Ear J, Farquhar MG. A structural determinant that renders G alpha(i) sensitive to activation by GIV/girdin is required to promote cell migration. J Biol Chem. 2010 Apr 23; 285(17):12765-77.
    View in: PubMed
  14. Garcia-Marcos M, Ghosh P, Farquhar MG. GIV is a nonreceptor GEF for G alpha i with a unique motif that regulates Akt signaling. Proc Natl Acad Sci U S A. 2009 Mar 3; 106(9):3178-83.
    View in: PubMed
  15. Garcia-Marcos M, Dehaye JP, Marino A. Membrane compartments and purinergic signalling: the role of plasma membrane microdomains in the modulation of P2XR-mediated signalling. FEBS J. 2009 Jan; 276(2):330-40.
    View in: PubMed
  16. Ghosh P, Garcia-Marcos M, Bornheimer SJ, Farquhar MG. Activation of Galphai3 triggers cell migration via regulation of GIV. J Cell Biol. 2008 Jul 28; 182(2):381-93.
    View in: PubMed
  17. Seil M, Fontanils U, Etxebarria IG, Pochet S, Garcia-Marcos M, Marino A, Dehaye JP. Pharmacological evidence for the stimulation of NADPH oxidase by P2X(7) receptors in mouse submandibular glands. Purinergic Signal. 2008 Dec; 4(4):347-55.
    View in: PubMed
  18. Pochet S, Garcia-Marcos M, Seil M, Otto A, Marino A, Dehaye JP. Contribution of two ionotropic purinergic receptors to ATP responses in submandibular gland ductal cells. Cell Signal. 2007 Oct; 19(10):2155-64.
    View in: PubMed
  19. Garcia-Marcos M, Pochet S, Marino A, Dehaye JP. P2X7 and phospholipid signalling: the search of the "missing link" in epithelial cells. Cell Signal. 2006 Dec; 18(12):2098-104.
    View in: PubMed
  20. Pochet S, Tandel S, Querriére S, Tre-Hardy M, Garcia-Marcos M, De Lorenzi M, Vandenbranden M, Marino A, Devleeschouwer M, Dehaye JP. Modulation by LL-37 of the responses of salivary glands to purinergic agonists. Mol Pharmacol. 2006 Jun; 69(6):2037-46.
    View in: PubMed
  21. Garcia-Marcos M, Pérez-Andrés E, Tandel S, Fontanils U, Kumps A, Kabré E, Gómez-Muñoz A, Marino A, Dehaye JP, Pochet S. Coupling of two pools of P2X7 receptors to distinct intracellular signaling pathways in rat submandibular gland. J Lipid Res. 2006 Apr; 47(4):705-14.
    View in: PubMed
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