of the Max - MDC

Structure of the Group
Group Leader
Prof. Dr. Walter Birchmeier
Scientists
Dr. Felix Brembeck
Dr. Marta De Rocha Rosário
Dr. Johannes Fritzmann
Dr. Katja Großmann
Dr. Klaus Hellmuth
Dr. Jane Holland*
Dr. Li Li
Dr. Michelle Lum*
Dr. Ute Schaeper*
Dr. Gunnar Schütz*
Dr. Dietmar Zechner*
Graduate Students
Özlem Akilli Öztürk*
Jolanta Chmielowiec
Tamara Grigoryan
Julian Heuberger*
Heinz Möller*
Alexandra Klaus
Regina Willecke*
Peter Wend
Diploma Student
Christien Bednarski
Technical Assistants
Renate Franke*
Lysann Hinz
Frauke Kosel
Marion Müller
Carola Seyffarth*
Simone Stein*
Regina Vogel
Ingrid Walther*
Secretariat
Irmgard Wiznerowicz
* part of the period reported
new family of multiadaptor proteins with RhoGAP activity.
We show that NOMA-GAP is essential for NGF-stimulated
neuronal differentiation and for the regulation of the ERK5
MAP kinase and the Cdc42 signaling pathways downstream
of NGF. NOMA-GAP binds directly to the NGF receptor, TrkA,
and becomes tyrosine-phosphorylated upon receptor activation,
thus enabling recruitment and activation of the tyrosine
phosphatase SHP2. Recruitment of SHP2 is required for
the stimulation of neuronal process extension and for sustained
activation of ERK5 downstream of NOMA-GAP. In
addition, we show that NOMA-GAP promotes neurite outgrowth
by tempering activation of the Cdc42/PAK signaling
pathway in response to NGF. NOMA-GAP, through its dual
function as a multiadaptor and RhoGAP protein, thus plays
an essential role downstream of NGF in promoting neurite
outgrowth and extension.
Distinct Requirements for Gab1 in Met and EGF
Receptor Signaling in vivo
Ute Schaeper, Regina Vogel, Jolanta Chmielowiec, Jörg
Hülsken and Marta Rosário (MDC)
Gab1 functions by amplifying signal transduction downstream
of various receptor tyrosine kinases through recruitment
of multiple signaling effectors, including PI3K and
Shp2. Until now, the functional significance of individual
interactions in vivo was not known. We have generated
knock-in mice, which carried point mutations in either the
P13K-, or Shp2-binding sites of Gab1. We showed that different
effector interactions with Gab1 play distinct biological
roles downstream of Gab1 during the development of
different organs. Recruitment of PI3K by Gab1 is essential
for EGF receptor mediated embryonic eyelid closure and
keratinocyte migration, while the Gab1-Shp2 interaction is
crucial for Met receptor-directed placental development and
muscle progenitor cell migration to the limbs. Furthermore,
we investigated the dual association of Gab1 with the Met
receptor. By analyzing knock-in mice with mutations in the
Grb2- or Met-binding site of Gab1, we showed that the
requirements for Gab1 recruitments to Met varies in different
biological contexts. Either the direct or the indirect
interaction of Gab1 with Met is sufficient for Met-dependent
muscle precursor cell migration, while both modes of interaction
are required, and neither is sufficient for placenta
development, liver growth and palatal shelf closure. These
data demonstrated that Gab1 induces different biological
responses through the recruitment of distinct effectors and
that different modes of recruitment for Gab1 are required in
different organs.
Selected Publications
Moeller, H, Jenny, A, Schaeffer, H-J, Schwarz-Romond, T,
Mlodzik, M, Hammerschmidt, M, and Birchmeier, W. (2006):
Diversin regulates heart formation and gastrulation movements
in development. Proc. Natl. Acad. Sci. USA 103, 15900-15905.
Zechner, D, Mueller, T, Wende, H, Walther, I, Taketo, MM,
Crenshaw III, BE, Treier, M, Birchmeier, W, Birchmeier, C.
(2007). Bmp and Wnt/β-catenin signals control expression of
the transcription factor Olig3 and the specification of spinal cord
neurons. Dev. Biol. 303, 181-190.
Chmielowiec, J, Borowiak, M, Morkel, M, Stradal, T, Munz, B,
Werner, S, Wehland, J, Birchmeier, C, Birchmeier, W. (2007).
c-Met is essential for wound healing in the skin. J. Cell Biol.
177, 151-162.
Rosário, M, Franke, R, Bednarski, C, and Birchmeier, W. (2007):
The Neurite-Outgrowth MultiAdaptor RhoGAP, NOMA-GAP, regulates
neurite extension through SHP2 and Cdc42. J. Cell Biol.,
178, 503-516.
Klaus, A, Saga, Y, Taketo, MM, Tzahor, E and Birchmeier, W.
(2007). Distinct roles of Wnt/β-catenin and Bmp signaling
during early cardiogenesis. Proc. Natl. Acad. Sci. USA. 104,
18531-18536.
Schaeper, U, Vogel, R, Chmielowiec, J, Huelsken, J, Rosário, M,
and Birchmeier, W. (2007). Distinct requirements for Gab1 in
Met and EGF receptor signaling in vivo. Proc. Natl. Acad. Sci.
USA, 104, 15376-15381.
Patent
MDC 0501: Shp-2 inhibitors, pharmaceutical compositions comprising
them and their use for treating phosphatase-mediated
diseases. W. Birchmeier, K. Hellmuth. EP 05 090 160.2.
80 Cancer Research