A Matriptase-Prostasin Reciprocal Zymogen Activation Complex with Unique Features: PROSTASIN AS A NON-ENZYMATIC CO-FACTOR FOR MATRIPTASE ACTIVATION

TY - JOUR

T1 - A Matriptase-Prostasin Reciprocal Zymogen Activation Complex with Unique Features

T2 - PROSTASIN AS A NON-ENZYMATIC CO-FACTOR FOR MATRIPTASE ACTIVATION

AU - Friis, Stine

AU - Uzzun Sales, Katiuchia

AU - Godiksen, Sine

AU - Peters, Diane E

AU - Lin, Chen-Yong

AU - Vogel, Lotte K

AU - Bugge, Thomas H

PY - 2013

Y1 - 2013

N2 - Matriptase and prostasin are part of a cell surface proteolytic pathway critical for epithelial development and homeostasis. Here we have used a reconstituted cell-based system and transgenic mice to investigate the mechanistic interrelationship between the two proteases. We show that matriptase and prostasin form a reciprocal zymogen activation complex with unique features. Prostasin serves as a critical co-factor for matriptase activation. Unexpectedly, however, prostasin-induced matriptase activation requires neither prostasin zymogen conversion nor prostasin catalytic activity. Prostasin zymogen conversion to active prostasin is dependent on matriptase but does not require matriptase zymogen conversion. Consistent with these findings, wild type prostasin, activation cleavage site-mutated prostasin, and catalytically inactive prostasin all were biologically active in vivo when overexpressed in the epidermis of transgenic mice, giving rise to a severe skin phenotype. Our finding of non-enzymatic stimulation of matriptase activation by prostasin and activation of prostasin by the matriptase zymogen provides a tentative mechanistic explanation for several hitherto unaccounted for genetic and biochemical observations regarding these two membrane-anchored serine proteases and their downstream targets.

AB - Matriptase and prostasin are part of a cell surface proteolytic pathway critical for epithelial development and homeostasis. Here we have used a reconstituted cell-based system and transgenic mice to investigate the mechanistic interrelationship between the two proteases. We show that matriptase and prostasin form a reciprocal zymogen activation complex with unique features. Prostasin serves as a critical co-factor for matriptase activation. Unexpectedly, however, prostasin-induced matriptase activation requires neither prostasin zymogen conversion nor prostasin catalytic activity. Prostasin zymogen conversion to active prostasin is dependent on matriptase but does not require matriptase zymogen conversion. Consistent with these findings, wild type prostasin, activation cleavage site-mutated prostasin, and catalytically inactive prostasin all were biologically active in vivo when overexpressed in the epidermis of transgenic mice, giving rise to a severe skin phenotype. Our finding of non-enzymatic stimulation of matriptase activation by prostasin and activation of prostasin by the matriptase zymogen provides a tentative mechanistic explanation for several hitherto unaccounted for genetic and biochemical observations regarding these two membrane-anchored serine proteases and their downstream targets.

U2 - 10.1074/jbc.M113.469932

DO - 10.1074/jbc.M113.469932

M3 - Journal article

C2 - 23673661

SN - 0021-9258

VL - 288

SP - 19028

EP - 19039

JO - The Journal of Biological Chemistry

JF - The Journal of Biological Chemistry

IS - 26

ER -