Head


Peter Herrlich
Peter Herrlich

Postdocs

Monika Hartmann

Vivienne Olaku

Vasily Romanov

PhD Students

Daniela Reich

Christina Lindner

Anne Lorenz

Technicians

Birgit Pavelka

Silke Schulz



 

Herrlich Research Group

Peter Herrlich, M.D.; Ph.D. Professor of Molecular Biology, is Scientific Director Emeritus of the Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI) since February 2012.


Cancer cell biology

The Herrlich Laboratory: The control of cellular migration and growth

How do embryonic cells start migrating, what governs migration of stem cells during regeneration, how do tumor cells metastasize. This is at the core of the lab┤s interest. Currently two genes are in the research focus: CD44 and Trip6.

 

CD44: the gene for CD44 is multiply alternatively spliced, therefore encodes a large family of type I transmembrane proteins. The splice variation addresses the extracellular portion. One of the splice variants, CD44v6 serves as an essential co-receptor for a tyrosine kinase which regulates migration: Met. In addition, CD44 mediates contact inhibition, the signal which makes cells stop growing, and CD44 may act also as tumor suppressor. This seemingly contradictory panel of actions need to be dissected. CD44 is also cleaved by g-secretase, like the Alzheimer APP protein. The cytoplasmic tail is taken up into the nucleus and activates a gene expression program involved in migration. We wish to find out, what regulates the cleavage and what exactly is the function in the nucleus. The methods include cellular and mouse models, structural biology and the identification of interference strategies, e.g. in order to prevent cleavage or to inhibit metastasis formation.

 

Trip6: Trip6 was discovered as a protein interacting with nuclear receptors. The nuclear form is generated by alternative translational start which eliminates the nuclear export sequence. The long form is located at focal adhesions at the plasma membrane. Suppression of the nuclear form reduces the efficiency of transcription driven by the Fos:Jun or NF-kB transcription factors and inhibits the antiinflammatory action of the glucocorticoid receptor. Nuclear Trip6 appears to serve as a platform on promoters by interaction with Fos, p65 (NF-kB) and nuclear receptors. The puzzle is, how it confers activating and repressing function. Both the nuclear and the cytoplasmic Trip6 isoforms appear to be engaged in growth control and migration.

 

Viral oncogenesis

Adenoviruses can transform rodent cells, catalyzed by the nuclear viral oncogenes E1A and E1B. We discovered a new action of E1A. It activates the Jun N-terminal kinase pathway and thus induces the transcription of Jun and ATF2 dependent genes. It appears that a small fraction of E1A is not in the nucleus, but rather at the plasma membrane where it causes the GTP loading and thus activation of the small G-proteins Rac and Cdc42. We wish to find out, how E1A does this. The methodology involves protein interaction screens and biochemical analysis, e.g. assays for guanine exchange factors and GTPase activating proteins.

 

Redox regulation of protein tyrosine phosphatases

Protein tyrosine phosphatases (PTPs) just like tyrosine kinases regulate numerous processes in cells. Their active enzyme centre carries a redox-sensitive cysteine and it is believed that inactivation by oxidation and activation by reduction is physiologically used for regulation. We found, however, that oxidative treatments by irradiating cells induces a calpain-dependent cleavage of PTPs. The current goal is to explore the mechanism and role of this cleavage reaction.

 

 

Inhouse collaborations with Aspasia Ploubidou, Zhao-Qi Wang, Helen Morrison, Jan Tuckermann, external collaboration with Frank Boehmer, Jena, and Olivier Kassel, Karlsruhe.

 

Recent selected publications

  • Morrison H, Sperka T, Manent J, Giovannini M, Ponta H, Herrlich P (2007) Merlin/neurofibromatosis type 2 suppresses growth by inhibiting the activation of Ras and Rac. Cancer Res, 67, 520-527. [PubMed]
  • Orian-Rousseau V, Morrison H, Matzke A, Kastilan T, Pace G, Herrlich P, Ponta H (2007) Hepatocyte growth factor-induced Ras activation requires ERM proteins linked to both CD44v6 and F-actin. Mol Biol Cell, 18, 76-83. [PubMed]
  • Jin H, Sperka T, Herrlich P, Morrison H (2006) Tumorigenic transformation by CPI-17 through inhibition of a merlin phosphatase. Nature, 442, 576-579. [PubMed]
  • Matzke A, Herrlich P, Ponta H, Orian-Rousseau V (2005) A five-amino-acid peptide blocks Met- and Ron-dependent cell migration. Cancer Res, 65, 6105-6110. [PubMed]
  • Pust S, Morrison H, Wehland J, Sechi AS, Herrlich P (2005) Listeria monocytogenes exploits ERM protein functions to efficiently spread from cell to cell. EMBO J, 24, 1287-1300. [PubMed]
  • Fieber C, Baumann P, Vallon R, Termeer C, Simon JC, Hofmann M, Angel P, Herrlich P, Sleeman JP (2004) Hyaluronan-oligosaccharide-induced transcription of metalloproteases. J Cell Sci, 117, 359-367. [PubMed]
  • Kassel O, Schneider S, Heilbock C, Litfin M, Göttlicher M, Herrlich P (2004) A nuclear isoform of the focal adhesion LIM-domain protein Trip6 integrates activating and repressing signals at AP-1- and NF-κB-regulated promoters. Genes Dev, 18, 2518-2528. [PubMed]
  • Herrlich P, Morrison H, Sleeman J, Orian-Rousseau V, König H, Weg-Remers S, Ponta H (2000) CD44 acts both as a growth- and invasiveness-promoting molecule and as a tumor-suppressing cofactor. Ann NY Acad Sci, 910, 106-118. [PubMed]

 


Last update: February 4, 2014

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