Huber Lukas A., Univ.-Prof. Dr.med.univ.

University / Clinic: Innsbruck Medical University
Institute: Biocenter, Division of Cell Biology
 
Research Area: Cell Biology

Email: lukas.a.huber@i-med.ac.at
Web: www.i-med.ac.at/cellbio/


Research Topic:
For many years, it was thought that signaling from receptor tyrosine kinases (RTKs) to MAP kinase (ERK) occurred only at the plasma membrane and was mediated by a simple, linear Ras dependent pathway. However, the limitation of this model became apparent with the discovery that Ras and ERK can be activated at various intracellular compartments, and that RTKs can modulate Ras/ERK signaling from these sites. Moreover, ERK scaffolding proteins and signaling modulators have been identified that play critical roles in determining the strength, duration and location of RTK-mediated ERK signaling. In this application we focus on the pathophysiological role of the late endosomal p14/MP1 scaffold complex. Interestingly, loss or mislocalization of the p14/MP1 complex was found to have no significant effect on the early activation of ERK at the plasma membrane, but it did alter the sustained ERK activation seen on endosomes. More recently, conditional disruption of p14 in mice has been found to impair late endosomal trafficking as well as endosomal ERK activation, resulting in cell proliferation defects that disrupt early embryogenesis and tissue homeostasis (Teis et al., 2006). Our aim for the second funding period is to provide further evidence that endosomal ERK signalling has important consequences in the regulation of cell proliferation, cell death and cell migration in tumor cells. купить полотенце киев


Interested in intracellular trafficking and cell sorting processes, we recently built up a second project where we investigate a protein, the Myosin Vb motor protein, a protein which is essential for intracellular trafficking and cell sorting processes in epithelial cells. The reason for that was the finding of missens and nonsense mutations in the MYO5b gen in patients with Microvilli inclusion disease (MVID), a very severe genetic disease of young children, characterized by life threatening malabsorption syndrome and watery diahrrea during infancy, (Mueller et al., 2008, Ruemmele et al, 2010). Our aim is to understand completely loss of function of Myosin Vb in epithelial cells.
In a conditional knock out mouse model, where the essential part of the protein will be deleted, effects of loss of Myosin Vb will be investigated first in the small intestine to mimic the main clinical phenotype of MVID patients in vivo, and after also in other epithelial tissues to see, if loss of Myosin Vb will disrupt intracellular trafficking processes also in other types of epithelial cells, in which the patients do not have clinical manifested phenotypes, but where it is known that this protein has regulatory functions in intracellular transporting and cell sorting mechanisms.
In an intestinal epithelial cell model with a transient Myosin Vb knock down, the main pathological hallmarks of MVID patients were already successfully demonstrated (Ruemmele et al, 2010). Now we establish an intestinal epithelial cell line with a stable or an inducible Myosin Vb knock down to investigate in more detail the role of Myosin Vb in epithelial cells, not only in trafficking processes, but also in regulation of different pathways for complete understanding of the pathogenesis of Microvilli inclusion disease on the molecular cell level and maybe to find new therapeutic targets for the treatment of MVID patients полотенце купить




Project:
  Novel Interaction between LAMTOR and BLOC1 Complexes
details ...

Selected publications:
 
  Janecke A, Xu R, Steichen-Gersdorf E, Waldegger S, Entenmann A, Giner T, Krainer I, Huber L, Hess M, Frishberg Y, Barash H, Tzur S, Schreyer-Shafir N, Sukenik-Halevy R, Zehavi T, Raas-Rothschild A, Mao C, Müller T
Deficiency of the sphingosine-1-phosphate lyase SGPL1 is associated with congenital nephrotic syndrome and congenital adrenal calcifications
Hum Mutat. 2017 Apr;38(4):365-372. doi: 10.1002/humu.23192. Epub 2017 Mar 6.

  Vogel G, Janecke A, Krainer I, Gutleben K, Witting B, Mitton S, Mansour S, Ballauff A, Roland J, Engevik A, Cutz E, Müller T, Goldenring J, Huber L, Hess M
Abnormal Rab11-Rab8-vesicles cluster in enterocytes of patients with Microvillus Inclusion Disease
Traffic. 2017 Apr 13. doi: 10.1111/tra.12486. [Epub ahead of print]

  Lammirato A, Patsch K, Feiereisen F, Maly K, Nofziger C, Paulmichl M, Hackl H, Trajanoski Z, Valovka T, Huber L, Vietor I
TIS7 induces transcriptional cascade of methylosome components required for muscle differentiation
BMC Biol. 2016 Oct 25;14(1):95.

  Rebsamen M, Pochini L, Stasyk T, de Araújo M, Galluccio M, Kandasamy R, Snijder B, Fauster A, Rudashevskaya E, Bruckner M, Scorzoni S, Filipek P, Huber K, Bigenzahn J, Heinz L, Kraft C, Bennett K, Indiveri C, Huber L, Superti-Furga G
SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1.
Nature. 2015 Mar 26;519(7544):477-81

  Vogel G, Ebner H, de Araujo M, Schmiedinger T, Eiter O, Pircher H, Gutleben K, Witting B, Teis D, Huber L, Hess M
Ultrastructural Morphometry Points to a New Role for LAMTOR2 in Regulating the Endo/Lysosomal System
Traffic. 2015 Jun;16(6):617-34. doi: 10.1111/tra.12271.

  Schiefermeier N, Scheffler J, de Araújo M, Stasyk T, Yordanov T, Ebner H, Offterdinger M, Munck S, Hess M, Wickström S, Lange A, Wunderlich W, Fässler R, Teis D, Huber L
The late endosomal p14-MP1 (LAMTOR2/3) complex regulates focal adhesion dynamics during cell migration.
J Cell Biol. 2014 May 26;205(4):525-40.

  de Araújo M, Stasyk T, Taub N, Ebner H, Fürst B, Filipek P, Weys S, Hess M, Lindner H, Kremser L, Huber L
Stability of the Endosomal Scaffold Protein LAMTOR3 Depends on Heterodimer Assembly and Proteasomal Degradation
J Biol Chem. 2013 Jun 21;288(25):18228-42

  Thöni C, Vogel G, Tancevski I, Geley S, Lechner S, Pfaller K, Hess MW, Müller T, Janecke A, Avitzur Y, Muise A, Cutz E, Huber L
Microvillus inclusion disease: loss of Myosin vb disrupts intracellular traffic and cell polarity.
Traffic. 2014 Jan;15(1):22-42.

  Alonso Y Adell M, Westerman B, Braat A, Taub N, Potman M, Vissers J, Blom M, Verhoeven E, Stoop H, Gillis A, Velds A, Nijkamp W, Beijersbergen R, Huber L, Looijenga L, van Lohuizen M
A genome-wide RNAi screen in mouse embryonic stem cells identifies Mp1 as a key mediator of differentiation.
J Exp Med. 2011 Dec 19;208(13):2675-89. Epub 2011 Dec 5.

  Skvortsov S, Schäfer G, Stasyk T, Fuchsberger C, Bonn G, Bartsch G, Klocker H, Huber L
Proteomics profiling of microdissected low- and high-grade prostate tumors identifies Lamin A as a discriminatory biomarker.
J Proteome Res. 10:259-68, 2011.

  Prokudin I, Stasyk T, Rainer J, Bonn G, Kofler R, Huber L
Comprehensive proteomic and transcriptomic
characterization of hepatic expression signatures affected in p14 liver conditional knockout mice
Proteomics. 2011 Feb;11(3):469-80. doi: 10.1002/pmic.201000400. Epub 2011 Jan 11

  Stasyk T, Holzmann J, Stumberger S, Ebner H, Hess M, Bonn G, Mechtler K, Huber L
Proteomic analysis of endosomes from genetically modified p14/MP1 mouse embryonic fibroblasts.
in press

  Soeno Y, Taya Y, Stasyk T, Huber L, Aoba T, Hüttenhofer A
Identification of novel ribonucleo-protein complexes from the brain-specific snoRNA MBII-52.
RNA. 2010 Jul;16(7):1293-300. Epub 2010 May 19.PMID: 20484469

  Huber L
Do pharmacogenetics, genomics and epigenetics hold promise for molecular therapeutics and health?
Curr Opin Mol Ther. 2010 Jun;12(3):268-9.PMID: 20556904

  Skvortsova I, Skvortsov S, Raju U, Stasyk T, Riesterer O, Schottdorf E, Popper B, Schiestl B, Eichberger P, Debbage P, Neher A, Bonn G, Huber L, Milas L, Lukas P
Epithelial-to-mesenchymal transition and c-myc expression are the determinants of cetuximab-induced enhancement of squamous cell carcinoma radioresponse.
Radiother Oncol. 2010 Jul;96(1):108-15. Epub 2010 May 5.PMID: 20451273

  Morandell S, Grosstessner-Hain K, Roitinger E, Hudecz O, Lindhorst T, Teis D, Wrulich O, Mazanek M, Taus T, Ueberall F, Mechtler K, Huber L
QIKS--Quantitative identification of kinase substrates.
Proteomics. 2010 May;10(10):2015-25.PMID: 20217869

  Hermann-Kleiter N, Gruber T, Lutz-Nicoladoni C, Thuille N, Fresser F, Labi V, Schiefermeier N, Warnecke M, Huber L, Villunger A, Eichele G, Kaminski S, Baier G.
The Nuclear Orphan Receptor NR2F6 Suppresses Lymphocyte Activation and T Helper 17-Dependent Autoimmunity
Immunity

  Hermann-Kleiter N, Gruber T, Lutz-Nicoladoni C, Thuille N, Fresser F, Labi V, Schiefermeier N, Warnecke M, Huber LA, Villunger A, Eichele G, Kaminski S, Baier G
The Nuclear Orphan Receptor NR2F6 Suppresses Lymphocyte Activation and T Helper 17-Dependent Autoimmunity.
Immunity. 2008 Aug;29(2):205-16

  Hermann-Kleiter N, Gruber T, Lutz-Nicoladoni C, Thuille N, Fresser F, Labi V, Schiefermeier N, Warnecke M, Huber L, Villunger A, Eichele G, Kaminski S, Baier G
The Nuclear Orphan Receptor NR2F6 Suppresses Lymphocyte Activation and T Helper 17-Dependent Autoimmunity.

Immunity. 2008 Aug;29(2):205-16

  Jurgeit A, Berlato C, Obrist P, Ploner C, Massoner P, Schmölzer J, Haffner M, Klocker H, Huber L, Geley S, Doppler W
Insulin-Like Growth Factor Binding Protein (Igfbp)-5 Enters Vesicular Structures but Not the Nucleus.
Traffic 8(12):1815-1828

  Teis D, Kurzbauer R, Hilber D, Erlacher M, Villunger A, Geley S, Bohn G, Klein C, Hess M, Huber L
The p14/MP1-scaffold complex is required for endosomal ERK activation and cell cycle progression in vivo.
J Cell Biol. 2006 Dec 18;175(6):861-8.

  Teis D, Taub N, Kurzbauer R, Hilber D, de Araujo M, Erlacher M, Offterdinger M, Villunger A, Geley S, Bohn G, Klein C, Hess M, Huber L
p14-MP1-MEK1 signaling regulates endosomal traffic and cellular proliferation during tissue homeostasis.
J Cell Biol. 2006 Dec 18;175(6):861-

  Feuerstein I, Morandell S, Stecher G, Huck C, Stasyk T, Huang H, Teis D, Huber L, Bonn G
Phosphoproteomic analysis using immobilized metal ion affinity chromatography on the basis of cellulose powder
Proteomics 2005, 5, 46–54

  Teis D, Kurzbauer R, Hilber D, Erlacher M, Villunger A, Geley S, Bohn G, Klein C, Hess M, Huber L
The p14/MP1-scaffold complex is required for endosomal ERK activation and cell cycle progression in vivo
submitted

  Stasyk T, Morandell S, Bakry R, Feuerstein I, Huck C, Stecher G, Bonn G, Huber L
Quantitative detection of phosphoproteins by combination of two-dimensional difference gel electrophoresis and phosphospecific fluorescent staining.
Electrophoresis. 2005 Jul;26(14):2850-4.

  Stasyk T, Huber L
Zooming in: Fractionation strategies in proteomics
Proteomics 2004, 4, 3704–3716

  Kurzbauer R, Teis D, de Araujo M, Maurer-Stroh S, Eisenhaber F, Bourenkov G, Bartunik H, Hekman M, Rapp U, Huber L, Clausen T
Crystal structure of the p14/MP1 scaffolding complex: how a twin couple attaches mitogen-activated protein kinase signaling to late endosomes.
Proc Natl Acad Sci U S A. 2004 Jul 27;101(30):10984-9.

  Vietor I, Vadivelu S, Wick N, Cotton M, Seiser C, Wunderlich W, Fialka I, Brosch G, Huber L
TIS7 interacts with the mammalian SIN3 histone deacetylase complex in epithelial cells
EMBO J. , 21: 4621-4631.

  Teis D, Wunderlich W, Huber L
p14: Localization of the MP1 - MAPK scaffold complex to endosomes is mediated by p14 and required for signal transduction
Dev. Cell 6: 803-14.

  Wunderlich W, Fialka I, Alpi A, Teis D, Pfeifer A, Parton R, Lottspeich F, Huber L
A novel 14 kD protein interacts with the MAP kinase scaffold MP1 on a late endosomal/lysosomal compartment.
J. Cell Biol. 152: 765-776