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Two Faces of Cathepsin D: Physiological Guardian Angel and Pathological Demon.

Khalkhali-Ellis Z, Hendrix MJ - Biol Med (Aligarh) (2014)

Bottom Line: Specifically, deregulated synthesis, post-translational modifications and hyper-secretion of CatD, along with its mitogenic effects, are established hallmarks of cancer.This review outlines CatD's post-translational modifications, cellular trafficking, secretion and protein binding partners in normal mammary gland, and restates the "site-specific" function of CatD which is most probably dictated by its post-translational modifications and binding partners.Noteworthy, CatD's association with one of its binding partners in the context of drug sensitivity is highlighted, with the optimism that it could contribute to the development of more effective chemotherapeutic agent(s) tailored for individual patients.

View Article: PubMed Central - PubMed

Affiliation: Stanley Manne Children's Research Institute, Northwestern University Feinberg School of Medicine, 2300 Children's Plaza, Box 222, Chicago, Illinois, 60614-3394, USA.

ABSTRACT

Since its discovery as a lysosomal hydrolase, Cathepsin D (CatD) has been the subject of intensive scrutiny by numerous scientists. Those accumulated efforts have defined its biosynthetic pathway, structure, and companion proteins in the context of its perceived "house keeping" function. However, in the past two decades CatD has emerged as a multifunctional enzyme, involved in myriad biological processes beyond its original "housekeeping" role. CatD is responsible for selective and limited cleavage (quite distinct from non-specific protein degradation) of particular substrates vital to proper cellular function. These proteolytic events are critical in the control of biological processes, including cell cycle progression, differentiation and migration, morphogenesis and tissue remodeling, immunological processes, ovulation, fertilization, neuronal outgrowth, angiogenesis, and apoptosis. Consistent with the biological relevance of CatD, its deficiency, altered regulation or post-translational modification underlie important pathological conditions such as cancer, atherosclerosis, neurological and skin disorders. Specifically, deregulated synthesis, post-translational modifications and hyper-secretion of CatD, along with its mitogenic effects, are established hallmarks of cancer. More importantly, but less studied, is its significance in regulating the sensitivity to anticancer drugs. This review outlines CatD's post-translational modifications, cellular trafficking, secretion and protein binding partners in normal mammary gland, and restates the "site-specific" function of CatD which is most probably dictated by its post-translational modifications and binding partners. Noteworthy, CatD's association with one of its binding partners in the context of drug sensitivity is highlighted, with the optimism that it could contribute to the development of more effective chemotherapeutic agent(s) tailored for individual patients.

No MeSH data available.


Related in: MedlinePlus

(A) Schematic presentation of CatD promoter region. The TATA and GC sequences are represented by square boxes, five transcription start sites are indicated by arrows and their distance from the +1 nucleotide are indicated. (B) Pictorial presentation of proteolytic processing of pre-pro-CatD. CatD is synthesized in the ER as a pre-pro enzyme containing a signal peptide at its amino terminus. As the enzyme traverses the ER, it loses its signal peptide and is glycosylated at two N-glycosylation sites. The pro-enzyme is transported to the Golgi, tagged with Man-6-P for binding to Man-6-PR. The complex is transported across the Golgi and reaches the endosomal compartment. The acidic environment causes the release of the receptor and the pro-peptide is cleaved generating the single chain active enzyme. Further removal of seven amino acids generates the light chain and the heavy chain mature enzyme (please see the text). (C) Developmental regulation of CatD level and proteolytic processing in mouse mammary tissue. Cytosolic extracts prepared from the mammary gland at different stages of development were subjected to SDS-PAGE and Western blot analysis for the presence of CatD cleavage products. V: virgin, P: pregnant, LD: lactation days 1, 3 and 7, IND: involution days 1–15. Molecular mass of CatD proteolytic products are indicated on the right.
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Figure 1: (A) Schematic presentation of CatD promoter region. The TATA and GC sequences are represented by square boxes, five transcription start sites are indicated by arrows and their distance from the +1 nucleotide are indicated. (B) Pictorial presentation of proteolytic processing of pre-pro-CatD. CatD is synthesized in the ER as a pre-pro enzyme containing a signal peptide at its amino terminus. As the enzyme traverses the ER, it loses its signal peptide and is glycosylated at two N-glycosylation sites. The pro-enzyme is transported to the Golgi, tagged with Man-6-P for binding to Man-6-PR. The complex is transported across the Golgi and reaches the endosomal compartment. The acidic environment causes the release of the receptor and the pro-peptide is cleaved generating the single chain active enzyme. Further removal of seven amino acids generates the light chain and the heavy chain mature enzyme (please see the text). (C) Developmental regulation of CatD level and proteolytic processing in mouse mammary tissue. Cytosolic extracts prepared from the mammary gland at different stages of development were subjected to SDS-PAGE and Western blot analysis for the presence of CatD cleavage products. V: virgin, P: pregnant, LD: lactation days 1, 3 and 7, IND: involution days 1–15. Molecular mass of CatD proteolytic products are indicated on the right.

Mentions: The 5′ upstream region of CatD promoter contains several GC boxes and a TATAA sequence [15]. This mixed promoter directs two types of transcription: TATA-independent transcription starting at several sites upstream from the TATA box (directed by GC boxes and Sp1 factor), and TATA-dependent transcription initiating about 28 bp downstream from the TATA box (Figure 1A).


Two Faces of Cathepsin D: Physiological Guardian Angel and Pathological Demon.

Khalkhali-Ellis Z, Hendrix MJ - Biol Med (Aligarh) (2014)

(A) Schematic presentation of CatD promoter region. The TATA and GC sequences are represented by square boxes, five transcription start sites are indicated by arrows and their distance from the +1 nucleotide are indicated. (B) Pictorial presentation of proteolytic processing of pre-pro-CatD. CatD is synthesized in the ER as a pre-pro enzyme containing a signal peptide at its amino terminus. As the enzyme traverses the ER, it loses its signal peptide and is glycosylated at two N-glycosylation sites. The pro-enzyme is transported to the Golgi, tagged with Man-6-P for binding to Man-6-PR. The complex is transported across the Golgi and reaches the endosomal compartment. The acidic environment causes the release of the receptor and the pro-peptide is cleaved generating the single chain active enzyme. Further removal of seven amino acids generates the light chain and the heavy chain mature enzyme (please see the text). (C) Developmental regulation of CatD level and proteolytic processing in mouse mammary tissue. Cytosolic extracts prepared from the mammary gland at different stages of development were subjected to SDS-PAGE and Western blot analysis for the presence of CatD cleavage products. V: virgin, P: pregnant, LD: lactation days 1, 3 and 7, IND: involution days 1–15. Molecular mass of CatD proteolytic products are indicated on the right.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4318633&req=5

Figure 1: (A) Schematic presentation of CatD promoter region. The TATA and GC sequences are represented by square boxes, five transcription start sites are indicated by arrows and their distance from the +1 nucleotide are indicated. (B) Pictorial presentation of proteolytic processing of pre-pro-CatD. CatD is synthesized in the ER as a pre-pro enzyme containing a signal peptide at its amino terminus. As the enzyme traverses the ER, it loses its signal peptide and is glycosylated at two N-glycosylation sites. The pro-enzyme is transported to the Golgi, tagged with Man-6-P for binding to Man-6-PR. The complex is transported across the Golgi and reaches the endosomal compartment. The acidic environment causes the release of the receptor and the pro-peptide is cleaved generating the single chain active enzyme. Further removal of seven amino acids generates the light chain and the heavy chain mature enzyme (please see the text). (C) Developmental regulation of CatD level and proteolytic processing in mouse mammary tissue. Cytosolic extracts prepared from the mammary gland at different stages of development were subjected to SDS-PAGE and Western blot analysis for the presence of CatD cleavage products. V: virgin, P: pregnant, LD: lactation days 1, 3 and 7, IND: involution days 1–15. Molecular mass of CatD proteolytic products are indicated on the right.
Mentions: The 5′ upstream region of CatD promoter contains several GC boxes and a TATAA sequence [15]. This mixed promoter directs two types of transcription: TATA-independent transcription starting at several sites upstream from the TATA box (directed by GC boxes and Sp1 factor), and TATA-dependent transcription initiating about 28 bp downstream from the TATA box (Figure 1A).

Bottom Line: Specifically, deregulated synthesis, post-translational modifications and hyper-secretion of CatD, along with its mitogenic effects, are established hallmarks of cancer.This review outlines CatD's post-translational modifications, cellular trafficking, secretion and protein binding partners in normal mammary gland, and restates the "site-specific" function of CatD which is most probably dictated by its post-translational modifications and binding partners.Noteworthy, CatD's association with one of its binding partners in the context of drug sensitivity is highlighted, with the optimism that it could contribute to the development of more effective chemotherapeutic agent(s) tailored for individual patients.

View Article: PubMed Central - PubMed

Affiliation: Stanley Manne Children's Research Institute, Northwestern University Feinberg School of Medicine, 2300 Children's Plaza, Box 222, Chicago, Illinois, 60614-3394, USA.

ABSTRACT

Since its discovery as a lysosomal hydrolase, Cathepsin D (CatD) has been the subject of intensive scrutiny by numerous scientists. Those accumulated efforts have defined its biosynthetic pathway, structure, and companion proteins in the context of its perceived "house keeping" function. However, in the past two decades CatD has emerged as a multifunctional enzyme, involved in myriad biological processes beyond its original "housekeeping" role. CatD is responsible for selective and limited cleavage (quite distinct from non-specific protein degradation) of particular substrates vital to proper cellular function. These proteolytic events are critical in the control of biological processes, including cell cycle progression, differentiation and migration, morphogenesis and tissue remodeling, immunological processes, ovulation, fertilization, neuronal outgrowth, angiogenesis, and apoptosis. Consistent with the biological relevance of CatD, its deficiency, altered regulation or post-translational modification underlie important pathological conditions such as cancer, atherosclerosis, neurological and skin disorders. Specifically, deregulated synthesis, post-translational modifications and hyper-secretion of CatD, along with its mitogenic effects, are established hallmarks of cancer. More importantly, but less studied, is its significance in regulating the sensitivity to anticancer drugs. This review outlines CatD's post-translational modifications, cellular trafficking, secretion and protein binding partners in normal mammary gland, and restates the "site-specific" function of CatD which is most probably dictated by its post-translational modifications and binding partners. Noteworthy, CatD's association with one of its binding partners in the context of drug sensitivity is highlighted, with the optimism that it could contribute to the development of more effective chemotherapeutic agent(s) tailored for individual patients.

No MeSH data available.


Related in: MedlinePlus