University of California San Francisco
Helen Diller Family Comprehensive Cancer Center
Keith Mostov, MD, PhD

Keith Mostov, MD, PhD

Professor, Departments of Anatomy and Biochemistry/Biophysics, UCSF

Cancer Center Program Memberships

Affiliate Member

Research Summary

Formation and regeneration of epithelial organs.

The Mostov Lab wants to understand how the shape, structure, and size of organs are determined during development, as well as how we can use that knowledge to foster the regeneration of damaged organs. Epithelia are the most common type of tissue in animals. Epithelial cells form sheets of cells that line surfaces and internal cavities. Most internal organs, such as the respiratory, digestive, genito-urinary and vascular systems, consist of a network of tubes that are lined by a single layer of epithelial cells, surrounded by other tissue types, such as muscle, neurons and connective tissue. We are studying how these epithelial tubes form and how they regenerate. We are using as models the tubes in several mammalian organ systems, such as the kidney and digestive system.

We are particularly interested in how the size of tubes is regulated and how this impacts regeneration. For instance, the mammalian small intestine consists of villi that project into the lumen of the intestine to increase the surface area available to absorb nutrients from the intestinal lumen. In between the villi are crypts, outpouchings of the wall of the small intestine. Epithelial stem cells are located at the base of the crypts. Some daughters of the stem cells differentiate and move up the crypts into the villi and are eventually shed from the tips of the villi. A single crypt stem cell can regenerate an entire crypt-villus structure.

The small intestine grows enormously in length both in the embryo and after birth, reaching a length of about 6 meters in the adult human. However, the small intestine never regenerates in length, either in the embryo or after birth. If the small intestine is abnormally short for any reason, such as mutation, injury or surgery, it can never recover in length. This is in stark contrast to the ability of a single stem cell in the base of the crypt to regenerate the entire crypt-villus structure. Almost nothing is known about the mechanisms that control the length of the small intestine. We have found multiple genes that control the length of the small intestine and have used them to uncover several signaling pathways that regulate the length of the small intestine. These genes and pathways open the door to therapies to promote regeneration of the length of the small intestine.

Education

University of Chicago, B.A., 1976, Biology
New College, Oxford, Rhodes Scholar, 1976-77, Physiology
Rockefeller University, Ph.D., 1983, Cell Biology
Cornell University Medical College, M.D., 1984, Medicine

Honors & Awards

  • 1976
    Rhodes Scholar
  • 1985
    Charles Hood Foundation Award
  • 1989
    Searle Scholar
  • 1990
    Cancer Research Institute Investigator Award
  • 1991
    Charles E. Culpeper Foundation Scholar in Medical Science
  • 1991
    Edward Mallinckrodt Foundation Medical Scholar
  • 1992
    American Heart Association Established Investigator Award
  • 2002-2012
    NIAID MERIT Award
  • 2017
    American Society for Cell Biology Inaugural Fellow Lifetime Achievement

Selected Publications

  1. Yang J, Antin P, Berx G, Blanpain C, Brabletz T, Bronner M, Campbell K, Cano A, Casanova J, Christofori G, Dedhar S, Derynck R, Ford HL, Fuxe J, García de Herreros A, Goodall GJ, Hadjantonakis AK, Huang RJY, Kalcheim C, Kalluri R, Kang Y, Khew-Goodall Y, Levine H, Liu J, Longmore GD, Mani SA, Massagué J, Mayor R, McClay D, Mostov KE, Newgreen DF, Nieto MA, Puisieux A, Runyan R, Savagner P, Stanger B, Stemmler MP, Takahashi Y, Takeichi M, Theveneau E, Thiery JP, Thompson EW, Weinberg RA, Williams ED, Xing J, Zhou BP, Sheng G. Guidelines and definitions for research on epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2020 Jun; 21(6):341-352.
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  2. Yu W, Marshall WF, Metzger RJ, Brakeman PR, Morsut L, Lim W, Mostov KE. Simple Rules Determine Distinct Patterns of Branching Morphogenesis. Cell Syst. 2019 09 25; 9(3):221-227.
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  3. Román-Fernández Á, Roignot J, Sandilands E, Nacke M, Mansour MA, McGarry L, Shanks E, Mostov KE, Bryant DM. The phospholipid PI(3,4)P2 is an apical identity determinant. Nat Commun. 2018 11 28; 9(1):5041.
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  4. Kwon SH, Oh S, Nacke M, Mostov KE, Lipschutz JH. Adaptor protein CD2AP and L-type lectin LMAN2 regulate exosome cargo protein trafficking through the Golgi complex. J Biol Chem. 2017 10 06; 292(40):16523.
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  5. Datta A, Sandilands E, Mostov KE, Bryant DM. Fibroblast-derived HGF drives acinar lung cancer cell polarization through integrin-dependent RhoA-ROCK1 inhibition. Cell Signal. 2017 12; 40:91-98.
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  6. Gao L, Yang Z, Hiremath C, Zimmerman SE, Long B, Brakeman PR, Mostov KE, Bryant DM, Luby-Phelps K, Marciano DK. Afadin orients cell division to position the tubule lumen in developing renal tubules. Development. 2017 10 01; 144(19):3511-3520.
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  7. Ruch TR, Bryant DM, Mostov KE, Engel JN. Par3 integrates Tiam1 and phosphatidylinositol 3-kinase signaling to change apical membrane identity. Mol Biol Cell. 2017 01 15; 28(2):252-260.
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  8. Kwon SH, Oh S, Nacke M, Mostov KE, Lipschutz JH. Adaptor Protein CD2AP and L-type Lectin LMAN2 Regulate Exosome Cargo Protein Trafficking through the Golgi Complex. J Biol Chem. 2016 Dec 02; 291(49):25462-25475.
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  9. Nedvetsky PI, Zhao X, Mathivet T, Aspalter IM, Stanchi F, Metzger RJ, Mostov KE, Gerhardt H. cAMP-dependent protein kinase A (PKA) regulates angiogenesis by modulating tip cell behavior in a Notch-independent manner. Development. 2016 10 01; 143(19):3582-3590.
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  10. Kim M, M Shewan A, Ewald AJ, Werb Z, Mostov KE. p114RhoGEF governs cell motility and lumen formation during tubulogenesis through a ROCK-myosin-II pathway. J Cell Sci. 2015 Dec 01; 128(23):4317-27.
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  11. Peng J, Awad A, Sar S, Komaiha OH, Moyano R, Rayal A, Samuel D, Shewan A, Vanhaesebroeck B, Mostov K, Gassama-Diagne A. Phosphoinositide 3-kinase p110d promotes lumen formation through the enhancement of apico-basal polarity and basal membrane organization. Nat Commun. 2015 Jan 13; 6:5937.
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  12. Bryant DM, Roignot J, Datta A, Overeem AW, Kim M, Yu W, Peng X, Eastburn DJ, Ewald AJ, Werb Z, Mostov KE. A molecular switch for the orientation of epithelial cell polarization. Dev Cell. 2014 Oct 27; 31(2):171-87.
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  13. Nedvetsky PI, Emmerson E, Finley JK, Ettinger A, Cruz-Pacheco N, Prochazka J, Haddox CL, Northrup E, Hodges C, Mostov KE, Hoffman MP, Knox SM. Parasympathetic innervation regulates tubulogenesis in the developing salivary gland. Dev Cell. 2014 Aug 25; 30(4):449-62.
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  14. Tran CS, Eran Y, Ruch TR, Bryant DM, Datta A, Brakeman P, Kierbel A, Wittmann T, Metzger RJ, Mostov KE, Engel JN. Host cell polarity proteins participate in innate immunity to Pseudomonas aeruginosa infection. . 2014 May 14; 15(5):636-43.
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  15. Kwon SH, Liu KD, Mostov KE. Intercellular transfer of GPRC5B via exosomes drives HGF-mediated outward growth. Curr Biol. 2014 Jan 20; 24(2):199-204.
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  16. Cerruti B, Puliafito A, Shewan AM, Yu W, Combes AN, Little MH, Chianale F, Primo L, Serini G, Mostov KE, Celani A, Gamba A. Polarity, cell division, and out-of-equilibrium dynamics control the growth of epithelial structures. J Cell Biol. 2013 Oct 28; 203(2):359-72.
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  17. Rousso T, Shewan AM, Mostov KE, Schejter ED, Shilo BZ. Apical targeting of the formin Diaphanous in Drosophila tubular epithelia. Elife. 2013 Jul 09; 2:e00666.
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  18. Roignot J, Peng X, Mostov K. Polarity in mammalian epithelial morphogenesis. Cold Spring Harb Perspect Biol. 2013 Feb 01; 5(2).
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  19. Cai L, Mostov KE. Cell height: Tao rising. J Cell Biol. 2012 Dec 24; 199(7):1023-4.
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  20. Gálvez-Santisteban M, Rodriguez-Fraticelli AE, Bryant DM, Vergarajauregui S, Yasuda T, Bañón-Rodríguez I, Bernascone I, Datta A, Spivak N, Young K, Slim CL, Brakeman PR, Fukuda M, Mostov KE, Martín-Belmonte F. Synaptotagmin-like proteins control the formation of a single apical membrane domain in epithelial cells. Nat Cell Biol. 2012 Aug; 14(8):838-49.
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