10900 Euclid Ave, BRB 823
Cleveland, OH 44106
After receiving his B.S. in Chemical Engineering in 1972 from Grove City College, Dr. Gerken undertook graduate studies at Case Western Reserve Univ. where he was awarded his Ph.D. in Chemistry in 1977. He was awarded the Kathy Graub Memorial Research Fellowship by the Cystic Fibrosis Foundation in 1978 as a postdoctoral fellow in Dr. Dearborn’s laboratory in the Dept. of Pediatrics at CWRU. He was promoted to Instructor in 1980 and in 1983 he was appointed Assistant Professor of Biochemistry in Pediatrics. Dr. Gerken was promoted to Associate Professor in 1995 and in 2005 he was made a full Professor in the Departments of Pediatrics and Biochemistry. Dr. Gerken has been on the Editorial Board of the Journal of Biological Chemistry since 1998.
Biosynthesis of O-Linked Glycans
Glycoproteins containing heavily O-glycosylated, mucin-like, domains play important and diverse biological roles for example, protecting cell surfaces, modulating cell-cell interactions, targeting cellular proteins, regulating inflammatory and immune responses and in tumorogenisis and metastasis. In these glycoproteins O-glycosylated domains typically play critical functional roles, which rely on their extended structures and ability to be decorated by an array of glycan structures. The goals of our laboratory are to develop a detailed understanding of biosynthetic processes that regulate the unique glycosylation patterns of these heavily O-glycosylated domains. From these studies we will learn how O-glycosylation is modulated by peptide sequence and neighboring glycosylation and the extent that changes in glycosylation may alter the properties of these domains.
A very large family of ppGalNAc transferases (>16) initiates mucin-type O-glycan by adding N-acetylgalactosamine (GalNAc) to peptide Ser and Thr residues. Homologous family members are found over a range of species suggesting that certain ppGalNAc transferases may have unique substrate specificities evolutionarily maintained for the glycosylation of specific peptide sequences. Presently, the peptide substrate specificities of the ppGalNAc transferase family members are poorly characterized, leading to an inability to rationally predict or comprehend O-glycosylation. Our laboratory has developed several novel methods utilizing mucin derived peptides and random peptide substrates for evaluating the substrate specificity of these transferases. We have further developed a kinetic modeling approach capable of approximating the observed glycosylation patterns of the mucin peptide substrates. We have also shown that our modeling approach can also reproduce the in vivo substitution pattern of the peptide linked GalNAc by galactose, forming the so-called Core 1 base structure. With a fundamental understanding of ppGalNAc transferase specificity the identification of isoform-specific substrates, the creation of isoform-specific inhibitors, and the prediction of O-glycosylation sites will be made possible.
Ongoing studies in the Gerken lab include the comparison of ppGalNAc T specificity across species, the determination of glycopeptide substrate preferences and a collaboration with Dr. Stanford Markowitz at CWRU characterizing the properties and biological roles of a series of ppGalNAc Ts that are associated with human colon cancers. Studies are also in progress characterizing the substrate specificity of the purified Core 1 transferase along with several other GalNAc substituting transferases.
As a result of our work, a more complete understanding of the initial steps in the biosynthesis of O-glycans will be obtained. It is anticipated that these studies will lead to development of methods for the prediction of O-glycan structures in a site-specific manner. This work is funded by the National Cancer Institute of the National Institutes of Health and the Cystic Fibrosis Foundation.