Ann Erickson, PhD

• Erickson Lab Website
• Publication List

RESEARCH INTERESTS: Cellular Biochemistry: Secretion of Lysosomal Proteases by Transformed Cells

In many tumors, the synthesis and secretion of a particular lysosomal protease is increased relative to normal cells in the surrounding tissue. The secreted protease is thought to aid tumor cell metastasis by participating in the degradation of the extracellular matrix through which the cells must migrate in order to establish secondary tumors. During certain developmental processes such as spermatogenesis, normal cells also need to migrate. There is evidence of increased expression and secretion of lysosomal proteases during this process too. We hope to characterize this lysosomal enzyme secretion pathway and determine the structural signals that are responsible for moving enzymes normally stored intracellularly in lysosomes into the extracellular environment, where they may serve physiological functions not normally ascribed to lysosomal proteases.

In Kirsten-virus transformed mouse fibroblasts (KNIH), synthesis of the lysosomal cysteine protease procathepsin L is upregulated and significant quantities of the inactive proform of the protease, normally a transient precursor, are stored within cells. By electron microscopy, we have localized the intracellular proenzyme to Golgi stacks and to abundant large, dense-core multivesicular endosomes. Procathepsin L reaches these vesicles after undergoing self-aggregation in the trans Golgi, a step that requires the propeptide. The extensive precedent for secretion of the contents of multivesicular endosomes suggests that in response to signals, these protease-containing endosomes might fuse with the plasma membrane, a process that would dump a bolus of protease in a localized region outside a cell.

To understand the change in cellular targeting that occurs when synthesis of the protease increases, we are identifying cellular proteins that bind procathepsin L and thus potentially contribute to targeting the protease into the dense-core storage vesicles. We are also generating mutant forms of the lysosomal protease that fail to bind these cellular proteins in order to determine where the mutant proteins accumulate in cells due to a block in their targeting pathway. These studies, which utilize mammalian cell culture, molecular biology, polyacrylamide gel electrophoresis, western blotting, cell fractionation, immunofluorescence, affinity chromatography and yeast two-hybrid analysis, will help us understand the structural signals which are responsible for moving enzymes normally targeted to lysosomes into the extracellular environment.

RECENT PUBLICATIONS:

Godbold GD, Ahn K, Yeyeodu S, Lee LF, Ting JP, Erickson AH. Biosynthesis and intracellular targeting of the lysosomal aspartic proteinase cathepsin D. Adv Exp Med Biol. 1998;436:153-62. Review.

Baer GS, Ebert DH, Chung CJ, Erickson AH, Dermody TS. Mutant cells selected during persistent reovirus infection do not express mature cathepsin L and do not support reovirus disassembly. J Virol. 1999 Nov;73(11):9532-43.

Yeyeodu S, Ahn K, Madden V, Chapman R, Song L, Erickson AH. Procathepsin L self-association as a mechanism for selective secretion. Traffic. 2000 Sep;1(9):724-37.

Ahn K, Yeyeodu S, Collette J, Madden V, Arthur J, Li L, Erickson AH. An alternate targeting pathway for procathepsin L in mouse fibroblasts. Traffic. 2002 Feb;3(2):147-59.

Bocock JP, Edgell CJ, Marr HS, Erickson AH. Human proteoglycan testican-1 inhibits the lysosomal cysteine protease cathepsin
L. Eur J Biochem. 2003 Oct;270(19):4008-15.

Collette J, Ulku AS, Der CJ, Jones A, Erickson AH. Enhanced cathepsin L expression is mediated by different Ras effector pathways in fibroblasts and epithelial cells. Int J Cancer. 2004 Nov 1;112(2):190-9.

Collette J, Bocock JP, Ahn K, Chapman RL, Godbold G, Yeyeodu S, Erickson AH. Biosynthesis and alternate targeting of the lysosomal cysteine protease cathepsin L. Int Rev Cytol. 2004;241:1-51. Review.

Nepal RM, Mampe S, Shaffer B, Erickson AH, Bryant P. Cathepsin L maturation and activity is impaired in macrophages harboring M. avium and M. tuberculosis. Int Immunol. 2006 Jun;18(6):931-9. Epub 2006 Apr 24.

Erickson AH, Bocock JP. Targeting to lysosomes in mammalian cells: the biosynthetic and endocytic pathways. Methods Mol Biol. 2007;390:339-61.