The research in my laboratory is directed at understanding molecular mechanisms of vesicular trafficking and protein sorting. This fundamental process underlies synaptic transmission, which is critical for all brain processes and contributes to functions as basic as the development of neuronal architecture and learning/memory formation.
Endocytic trafficking pathways. Following internalization (1), cargo-containing vesicles fuse with the early endosome. At this point, proteins may be recycled to the plasma membrane via recycling endosomes (2) or may remain associated with the endosomal membrane as the early endosome matures into a late endosome/multivesicular body (MVB) (3). Proteins present on the limiting membrane of the MVB may be recycled to the plasma membrane following vesicle budding (not shown) or the MVB itself may fuse with the plasma membrane resulting in the secretion of exosomes (4, internal vesicles of the MVB). Following ESCRT-mediated, ubiquitin-dependent sorting of proteins on the limiting membrane, MVBs fuse with lysosomes resulting in the degradation of internal MVB vesicles and their contents (5). Late endosomes/MVBs can fuse with autophagosomes resulting in a hybrid organelle called an amphisome (6). Alternatively, autophagosomes can fuse directly with lysosomes. Amphisomes can fuse with lysosomes forming autolysosomes (7). (Click on the image for an enlarged version).
Additionally, the endocytic mechanisms responsible for sorting membrane proteins are also involved in enveloped virus (e.g., HIV and Ebola) budding, and some types of cancer, underscoring the essential and fundamental nature of this process.
Etoposide-loaded immunoliposomes as active targeting agents for GD2 positive malignancies. Brown, B.S., Patanam, T., Mobli, K., Celia, C., Zage, P.E., Bean, A.J.*, Tasciotti, E., Cancer Biology and Therapy, 15:1-11, 2014 PMID: 24755919.
UBE4B couples ubiquitination and sorting machineries to enable EGFR degradation. Sirisaengtaksin N, Gireud M, Yan Q, Kubota Y, Meza D, Waymire JC, Zage PE, Bean AJ. Journal of Biological Chemistry. 2014 Jan 31; 289(5):3026-39. PMID:24344129.
Mycobacterium tuberculosis Type VII Secreted Effector EsxH Targets Host ESCRT to Impair Trafficking. Mehra A, Zahra A, Thompson V, Sirisaengtaksin N, Wells A, et al. (2013) PLoS Pathog 9(10): e1003734. doi:10.1371/journal.ppat.1003734 PMID:24204276
Cellular communication via nanoparticle-transporting biovesicles. Ferrati S, McConnell KI, Mack AC, Sirisaengtaksin N, Diaz R, Bean AJ, Ferrari M, Serda RE Nanomedicine (Lond). 2013 Jun 3. PMID:23731456
UBE4B levels are correlated with clinical outcomes in neuroblastoma patients and with altered neuroblastoma cell proliferation and sensitivity to epidermal growth factor receptor inhibitors. Zage, P. E., Sirisaengtaksin, Natalie, Liu, Y., Gireud, Monica, Brown, Brandon S., Palla, S., Richards, K. N., Hughes, D. P. M. and Bean, A. J., Cancer. 2013 Feb 15;119(4):915-23. PMID:22990745
Cell-Free Reconstitution of Multivesicular Body Formation and Receptor Sorting. Sun W, Vida TA, Sirisaengtaksin N, Merrill SA, Hanson PI, Bean AJ. Traffic. 2010 Feb 27. PMID: 20214752
Rapid recycling of beta-adrenergic receptors is dependent on the actin cytoskeleton and myosin Vb. Millman EE, Zhang H, Zhang H, Godines V, Bean AJ, Knoll BJ, Moore RH. Traffic. 2008 Nov;9(11):1958-71. PMID: 18785920
The endosome-associated protein Hrs is hexameric and controls cargo sorting as a "master molecule". Pullan L, Mullapudi S, Huang Z, Baldwin PR, Chin C, Sun W, Tsujimoto S, Kolodziej SJ, Stoops JK, Lee JC, Waxham MN, Bean AJ, Penczek PA. Structure. 2006 Apr;14(4):661-71.PMID: 16615908
Hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) interacts with PELP1 and activates MAPK. Rayala SK, Hollander P, Balasenthil S, Molli PR, Bean AJ, Vadlamudi RK, Wang RA, Kumar R. J Biol Chem. 2006 Feb 17;281(7):4395-403. PMID: 16352611
CART: an Hrs/actinin-4/BERP/myosin V protein complex required for efficient receptor recycling. Yan Q, Sun W, Kujala P, Lotfi Y, Vida TA, Bean AJ. Mol Biol Cell. 2005 May;16(5):2470-82. PMID: 15772161
mVps24p functions in EGF receptor sorting/trafficking from the early endosome. Yan Q, Hunt PR, Frelin L, Vida TA, Pevsner J, Bean AJ. Exp Cell Res. 2005 Mar 10;304(1):265-73. PMID: 15707591
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