TY - JOUR
T1 - Diverse Substrate Recognition Mechanisms for Rhomboids
T2 - Thrombomodulin Is Cleaved by Mammalian Rhomboids
AU - Lohi, Olli
AU - Urban, Sinisa
AU - Freeman, Matthew
N1 - Funding Information:
We especially thank Jeff Lee for allowing us to cite his unpublished data that mammalian EGF-like ligands are not cleaved by rhomboids and for his help in the early stages of this project. Human thrombomodulin cDNA was generously provided by Gabriella Kunz and Evan Sadler and mouse RHBDL3 (ventrhoid) cDNA by Michael Brand. O.L. was a recipient of an EMBO Long Term Fellowship and was partly supported by the Academy of Finland. S.U. was a J.B. & Millicent Kaye Prize Fellow in Cancer Studies of Christ's College, Cambridge University and is the recipient of a long-term fellowship from the Human Frontier Science Program.
PY - 2004/2/3
Y1 - 2004/2/3
N2 - The rhomboids are a recently discovered family of intramembrane proteases that are conserved across evolution. Drosophila was the first organism in which they were characterized, where at least Rhomboids 1-3 activate EGF receptor signaling by releasing the active forms of EGF-like growth factors [1, 2]. Subsequent work has begun to shed light on the role of these proteases in bacteria and yeast [3-8], but nothing is known about the function of rhomboids in vertebrates beyond evidence that the subclass of mitochondrial rhomboids is conserved [4]. Here, we report that the anticoagulant cell-surface protein thrombomodulin [9] is the first mammalian protein to be a rhomboid substrate in a cell culture assay. The thrombomodulin transmembrane domain (TMD) is cleaved only by vertebrate RHBDL2-like rhomboids. Thrombomodulin TMD cleavage is directed not by sequences within the TMD, as is the case with Spitz but by its cytoplasmic domain, which, at least in some contexts, is necessary and sufficient to determine cleavage by RHBDL2. These data suggest that thrombomodulin could be a physiological substrate for rhomboid. Moreover, the discovery of a second mode of substrate recognition by rhomboids implies mechanistic diversity in this family of intramembrane proteases.
AB - The rhomboids are a recently discovered family of intramembrane proteases that are conserved across evolution. Drosophila was the first organism in which they were characterized, where at least Rhomboids 1-3 activate EGF receptor signaling by releasing the active forms of EGF-like growth factors [1, 2]. Subsequent work has begun to shed light on the role of these proteases in bacteria and yeast [3-8], but nothing is known about the function of rhomboids in vertebrates beyond evidence that the subclass of mitochondrial rhomboids is conserved [4]. Here, we report that the anticoagulant cell-surface protein thrombomodulin [9] is the first mammalian protein to be a rhomboid substrate in a cell culture assay. The thrombomodulin transmembrane domain (TMD) is cleaved only by vertebrate RHBDL2-like rhomboids. Thrombomodulin TMD cleavage is directed not by sequences within the TMD, as is the case with Spitz but by its cytoplasmic domain, which, at least in some contexts, is necessary and sufficient to determine cleavage by RHBDL2. These data suggest that thrombomodulin could be a physiological substrate for rhomboid. Moreover, the discovery of a second mode of substrate recognition by rhomboids implies mechanistic diversity in this family of intramembrane proteases.
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U2 - 10.1016/S0960-9822(04)00008-9
DO - 10.1016/S0960-9822(04)00008-9
M3 - Article
C2 - 14761657
AN - SCOPUS:1242288387
SN - 0960-9822
VL - 14
SP - 236
EP - 241
JO - Current Biology
JF - Current Biology
IS - 3
ER -