Identification and Characterization of Target Proteins of Microtubule-associated Protein Phosphatase 2A (PP2A)

• Applicant: Professorin Dr. Susann Schweiger
• Subject Area: Human Genetics
• Term: from 2004 to 2008
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5436477

Protein Phosphatase 2A (PP2A) is involved in countless cellular processes, whereby the specifity of its catalytic C-subunit is regulated by many different B-subunits. Moreover, conducted by these regulatory subunits, PP2A pools are found in different cellular compartments fulfilling specified functions there. While microtubule-association of a pool of PP2A could clearly be shown, little is known about function and regulation of microtubule-associated PP2A and putative target proteins of its serine/threonine phosphatase activity. Characterization of the MlD1 gene-product, which is responsible for the development of a ventral midline malformation phenotype in humans, the so-called Opitz BBB/G syndrome (OS), we have been able to demonstrate that the MlD1 protein triggers ubiquitin-specific modification and degradation of microtubule-associated proteins in a cell line derived from an OS fetus with a loss-of-function MlD1 mutation. Via phenotype comparisons of OS with different other monogenic disorders affecting the ventral midline, we could also demonstrate that human Fused (hFused) protein, an effector molecule in the sonic hedgehog (shh) pathway, is a target of microtubule-associated PP2A activity. This project aims at the further characterization of hFused phosphorylation and its consequences for the shh pathway. Moreover, comparative 2D-gel electrophoresis and subsequent mass spectrometry shall be used to identify additional targets of microtubule-associated PP2A.

• DFG Programme: Research Grants