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Ken Prehoda

Ken Prehoda

Professor, Chemistry and Biochemistry
Member, IMB

Ph.D., University of Wisconsin
B.A., California State University

Lab website
Office: Klamath Hall Room 291
Office Phone: 541-346-5030
Lab: Klamath Hall Room 290
Lab Phone: 541-346-5049

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Research Interests

Research in the Prehoda lab focuses on understanding the protein interaction networks that regulate stem cell divisions. The Drosophila neuroblast undergoes repeated asymmetric divisions to populate the fly central nervous system and is our primary model system. Following neuroblast division, one daughter cell retains the neuroblast fate while the other goes on to become neurons or glia. The foundation of this amazing process is the segregation of different fate determinant proteins into the two daughter cells during mitosis. Our work attempts to uncover the molecular basis of this stem cell division through the study of cell polarity and mitotic spindle orientation.

The first step in fate determinant segregation is their polarization, in which the proteins localize to opposite regions of the cell membrane. How does the cell become organized in this way? We have studied the Par complex, a set of three proteins that polarizes many different cell types, including neuroblasts. A kinase, atypical Protein Kinase C, is a key component of the Par complex, as attachment of a phosphate to downstream proteins polarizes them. We are trying to understand how cells control where the Par complex is localized, and how substrate phosphorylation leads to their polarization. Loss of polarity is a hallmark of cancer, and we are also studying the relationship between polarity and tumorigenesis.

Fate determinant polarization alone is not enough for the stem cell to function properly. The mitotic spindle must also align along the polarity axis so that the cleavage furrow will bisect the the two membrane domains containing different fate determinants. How is the position of the spindle specified? We are studying proteins that link the cell cortex with microtubule motors that generate forces on the spindle's astral microtubules.

We have also recently begun working on questions in molecular evolution. One of the spindle orienting proteins we've identified is a protein interaction domain that resembles the guanylate kinase (GK) enzyme, which catalyzes the formation of GDP from GMP and ATP. The GK domain version of the protein originated via a duplication of the enzyme sometime near the unicellular to multicellular transition that gave rise to animals (approximately 600 million years ago). How did a nucleotide kinase become a protein interaction domain? In collaboration with the Thornton and Harms labs, we have "resurrected" the ancient ancestors of these proteins so that they can be studied in the lab. This has allowed us to directly answer questions about this amazing functional transition. As the GK domain is a special type of protein interaction domain - a phosphoprotein recognition module - we are now studying how regulation evolved in this system.

Prehoda research Structures of PDZ domain complexes involved in stem cell division. On the left, the PDZ from the protein Par-6 is bound to a carboxy-terminal sequence (N and C-terminii of the ligand are labeled). This mode of binding is enforced by a steric mechanism ­ residues that would extend past the c-terminus would clash with residues from the domain itself. On the right, an internal sequence is shown bound to the Par-6 PDZ domain. This sequence bypasses the carboxy-terminal requirement by taking advantage of plasticity in the PDZ domain.

Recent publications

(pulled from pubmed)

Recent publications

(pulled from pubmed)

Ordered multisite phosphorylation of lethal giant larvae by atypical protein kinase C.
Graybill C, Prehoda KE
Biochemistry 2014 Aug 5;53(30):4931-7
Formin-mediated actin polymerization cooperates with Mushroom body defect (Mud)-Dynein during Frizzled-Dishevelled spindle orientation.
Johnston CA, Manning L, Lu MS, Golub O, Doe CQ, Prehoda KE
J Cell Sci 2013 Oct 1;126(Pt 19):4436-44
Inscuteable regulates the Pins-Mud spindle orientation pathway.
Mauser JF, Prehoda KE
PLoS One 2012;7(1):e29611
Partitioning-defective protein 6 (Par-6) activates atypical protein kinase C (aPKC) by pseudosubstrate displacement.
Graybill C, Wee B, Atwood SX, Prehoda KE
J Biol Chem 2012 Jun 15;287(25):21003-11
Structure of an enzyme-derived phosphoprotein recognition domain.
Johnston CA, Doe CQ, Prehoda KE
PLoS One 2012;7(4):e36014
Ultrasensitive synthetic protein regulatory networks using mixed decoys.
Lu MS, Mauser JF, Prehoda KE
ACS Synth Biol 2012 Feb 17;1(2):65-72
Microtubules in distress release arrest.
Prehoda KE
Dev Cell 2012 Aug 14;23(2):233-4
Asymmetric cortical extension shifts cleavage furrow position in Drosophila neuroblasts.
Connell M, Cabernard C, Ricketson D, Doe CQ, Prehoda KE
Mol Biol Cell 2011 Nov;22(22):4220-6
Conversion of the enzyme guanylate kinase into a mitotic-spindle orienting protein by a single mutation that inhibits GMP-induced closing.
Johnston CA, Whitney DS, Volkman BF, Doe CQ, Prehoda KE
Proc Natl Acad Sci U S A 2011 Nov 1;108(44):E973-8
Canoe binds RanGTP to promote Pins(TPR)/Mud-mediated spindle orientation.
Wee B, Johnston CA, Prehoda KE, Doe CQ
J Cell Biol 2011 Oct 31;195(3):369-76
Cell polarity: keeping worms LeGaL.
Prehoda KE, Bowerman B
Curr Biol 2010 Aug 10;20(15):R646-8
A spindle-independent cleavage furrow positioning pathway.
Cabernard C, Prehoda KE, Doe CQ
Nature 2010 Sep 2;467(7311):91-4
Multiple tail domain interactions stabilize nonmuscle myosin II bipolar filaments.
Ricketson D, Johnston CA, Prehoda KE
Proc Natl Acad Sci U S A 2010 Dec 7;107(49):20964-9
Allosteric control of regulated scaffolding in membrane-associated guanylate kinases.
Marcette J, Hood IV, Johnston CA, Doe CQ, Prehoda KE
Biochemistry 2009 Oct 27;48(42):10014-9
Polarization of Drosophila neuroblasts during asymmetric division.
Prehoda KE
Cold Spring Harb Perspect Biol 2009 Aug;1(2):a001388
Filament-dependent and -independent localization modes of Drosophila non-muscle myosin II.
Liu SL, Fewkes N, Ricketson D, Penkert RR, Prehoda KE
J Biol Chem 2008 Jan 4;283(1):380-7
Cdc42 acts downstream of Bazooka to regulate neuroblast polarity through Par-6 aPKC.
Atwood SX, Chabu C, Penkert RR, Doe CQ, Prehoda KE
J Cell Sci 2007 Sep 15;120(Pt 18):3200-6
Galphai generates multiple Pins activation states to link cortical polarity and spindle orientation in Drosophila neuroblasts.
Nipper RW, Siller KH, Smith NR, Doe CQ, Prehoda KE
Proc Natl Acad Sci U S A 2007 Sep 4;104(36):14306-11
Internal recognition through PDZ domain plasticity in the Par-6-Pals1 complex.
Penkert RR, DiVittorio HM, Prehoda KE
Nat Struct Mol Biol 2004 Nov;11(11):1122-7
How signaling proteins integrate multiple inputs: a comparison of N-WASP and Cdk2.
Prehoda KE, Lim WA
Curr Opin Cell Biol 2002 Apr;14(2):149-54