Biosynthesis and Intracellular Targeting of the Lysosomal Aspartic Proteinase Cathepsin D

Godbold, Gene D.; Ahn, Kyujeong; Yeyeodu, Susan; Lee, Li Fen; Ting, Jenny P.Y.; Erickson, Ann H.

doi:10.1007/978-1-4615-5373-1_21

Cited by 19 publications

(20 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Data from transient transfection studies presented here further support a relationship between ProCathD and PSAP. The two precursors PSAP and proCathD are glycoproteins that originate in the endoplasmic reticulum (ER) which travel together as a PSAP-proCathD complex and reach the lysosomes by intracellular trafficking [4,21,26,27]. In endosomal and/or lysosomal compartments, they undergo mutual proteolytic processing to become the final mature products, saposins and CathD.…”

Section: Discussionmentioning

confidence: 99%

Prosaposin down-modulation decreases metastatic prostate cancer cell adhesion, migration, and invasion

Delorme

Liu

et al. 2010

Mol Cancer

View full text Add to dashboard Cite

BackgroundFactors responsible for invasive and metastatic progression of prostate cancer (PCa) remain largely unknown. Previously, we reported cloning of prosaposin (PSAP) and its genomic amplification and/or overexpression in several androgen-independent metastatic PCa cell lines and lymph node metastases. PSAP is the lysosomal precursor of saposins, which serve as activators for lysosomal hydrolases involved in the degradation of ceramide (Cer) and other sphingolipids.ResultsOur current data show that, in metastatic PCa cells, stable down-modulation of PSAP by RNA-interference via a lysosomal proteolysis-dependent pathway decreased β1A-integrin expression, its cell-surface clustering, and adhesion to basement membrane proteins; led to disassembly of focal adhesion complex; and decreased phosphorylative activity of focal adhesion kinase and its downstream adaptor molecule, paxillin. Cathepsin D (CathD) expression and proteolytic activity, migration, and invasion were also significantly decreased in PSAP knock-down cells. Transient-transfection studies with β1A integrin- or CathD-siRNA oligos confirmed the cause and effect relationship between PSAP and CathD or PSAP and Cer-β1A integrin, regulating PCa cell migration and invasion.ConclusionOur findings suggest that by a coordinated regulation of Cer levels, CathD and β1A-integrin expression, and attenuation of "inside-out" integrin-signaling pathway, PSAP is involved in PCa invasion and therefore might be used as a molecular target for PCa therapy.

show abstract

Section: Discussionmentioning

confidence: 99%

Prosaposin down-modulation decreases metastatic prostate cancer cell adhesion, migration, and invasion

Delorme

Liu

et al. 2010

Mol Cancer

View full text Add to dashboard Cite

show abstract

“…Like the caspases, cathepsins are synthesized as inactive zymogens, and activation involves proteolytic processing. [9][10][11][12][13] As discussed below, the involvement of cathepsins in apoptotic cell death has primarily been studied in nonhematopoietic systems. Evidence from these systems, however, should provide the basis for investigating the role of cathepsins in the death of both normal and malignant hematopoietic cells.…”

Section: Cathepsins and Apoptosismentioning

confidence: 99%

Noncaspase proteases in apoptosis

2000

View full text Add to dashboard Cite

Biochemical and genetic analysis of apoptosis has determined that intracellular proteases are key effectors of cell death pathways. In particular, early studies have pointed to the primacy of caspase proteases as mediators of execution. More recently, however, evidence has accumulated that noncaspases, including cathepsins, calpains, granzymes, and the proteasome complex, also have roles in mediating and promoting cell death. An important goal is to understand the importance of distinct noncaspases in various forms of apoptosis, and to determine whether pathways mediated by noncaspase proteases intersect with those mediated by caspases. In this review the roles of noncaspase proteases in the biochemistry of apoptosis will be discussed. Leukemia (2000) 14, 1695-1703.

show abstract

“…Alternatively, they might be diverted towards the endo-lysosomal pathway where they could function by digestion of endocytosed agonist-bound receptors or proteins taken up from uterine secretions (uterotroph). Since both the identified PAGs seem to be somewhat selective in regard to substrate preference, it may be safe to hypothesize that the ancient PAGs do not function as general degradative enzymes like cathepsin D and E, which are lysosomal and endosomal peptidases, respectively (Godbold et al, 1998; Ishidoh and Kominami, 2002). Bovine PAG-2/-12 are constitutively secreted and accumulate at the maternal-fetal interface (Wooding et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

An examination of the proteolytic activity for bovine pregnancy-associated glycoproteins 2 and 12

Telugu

Palmier

Doren

et al. 2010

Biological Chemistry

View full text Add to dashboard Cite

The pregnancy-associated glycoproteins (PAGs) represent a complex group of putative aspartic peptidases expressed exclusively in the placentas of species in the Artiodactyla order. The ruminant PAGs segregate into two classes -the 'ancient' and 'modern' PAGs. Some of the modern PAGs possess alterations in the catalytic center that are predicted to preclude their ability to act as peptidases. The ancient ruminant PAGs in contrast are thought to be peptidases, although, no proteolytic activity has been described for these members. The goal of this present study was to investigate (1) if the ancient bovine PAGs (PAGs-2 and -12) have proteolytic activity, and (2) if there are any differences in activity between these two closely related members. Recombinant bovine PAGs-2 and -12 were expressed in a baculovirus expression system and the purified proteins were analyzed for proteolytic activity against a synthetic fluorescent cathepsin D/E substrate. Both proteins exhibited proteolytic activity with acidic pH optima. The k cat /K M for bovine PAG-2 was 2.7×10 5 M −1 s −1 and for boPAG-12 it was 6.8×10 4 M −1 s −1 . The enzymes were inhibited by pepstatin A with a K i of 0.56 and 7.5 nM for boPAG-2 and boPAG-12, respectively. This is the first report describing proteolytic activity in PAGs from ruminant ungulates.

show abstract

Biosynthesis and Intracellular Targeting of the Lysosomal Aspartic Proteinase Cathepsin D

Cited by 19 publications

References 41 publications

Prosaposin down-modulation decreases metastatic prostate cancer cell adhesion, migration, and invasion

Prosaposin down-modulation decreases metastatic prostate cancer cell adhesion, migration, and invasion

Noncaspase proteases in apoptosis

An examination of the proteolytic activity for bovine pregnancy-associated glycoproteins 2 and 12

Contact Info

Product

Resources

About