A mutation in aminopeptidase N (CD13) isolated from a patient suffering from leukemia leads to an arrest in the endoplasmic reticulum.
Human aminopeptidase N (APN) is used as a routine marker for myelomonocytic cells in hematopoietic malignant disorders. Its gene and surface expressions are increased in cases of malignant transformation, inflammation, or T cell activation, whereas normal B and resting T cells lack detectable APN protein expression. In this study we elucidated the intracellular distribution, expression pattern, and enzymatic activity of a naturally occurring mutation in the coding region of the APN gene. At physiological temperatures the mutant protein is enzymatically inactive, persists as a mannose-rich polypeptide in the endoplasmic reticulum, and is ultimately degraded by an endoplasmic reticulum-associated degradation pathway. It shows in part the distinct behavior of a temperature-sensitive mutant with a permissive temperature of 32 degrees C, leading to correct sorting of the Golgi compartment accompanied by the acquisition of proper glycosylation but without reaching the cell-surface membrane and without regaining its enzymatic activity. Because the patient bearing this mutation suffered from leukemia, possible links to the pathogenesis of leukemia are discussed.
Department of Physiological Chemistry, School of Veterinary Medicine, D-30559 Hannover, Germany. Marwan.Alfalah@tiho-hannover.de
Marwan
M
Alfalah
Michael P
MP
Krahn
Gabi
G
Wetzel
Stephan
S
von Hörsten
Carmen
C
Wolke
Nigel
N
Hooper
Thomas
T
Kalinski
Sabine
S
Krueger
Hassan Y
HY
Naim
Uwe
U
Lendeckel
D000368:Aged; D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D018826:CD13 Antigens / Q000235:genetics* / Q000378:metabolism; D019556:COS Cells / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002522:Chlorocebus aethiops; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006031:Glycosylation; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009154:Mutation / Q000235:genetics*; D014407:Tumor Cells, Cultured
D018826:CD13 Antigens