Proteolytic processing of human growth hormone by multiple tissue kallikreins and regulation by the serine protease inhibitor Kazal-Type5 (SPINK5) protein

Komatsu, Naoya; Saijoh, Kiyofumi; Otsuki, Norio; Kishi, Tadaaki; Micheal, Iacovos P.; Obiezu, Christina V.; Borgoño, Carla A.; Takehara, Kazuhiko; Jayakumar, Arumugam; Wu, Hua; Diamandis, Eleftherios P.

doi:10.1016/j.cca.2006.10.009

Cited by 33 publications

(30 citation statements)

References 51 publications

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“…Several KLKs, including KLK5, are known to cleave growth hormone (GH) and to be present in the pitu itary gland (Komatsu et al, 2007). It has been suggested that in NS patients the absence of LEKTI leads to higher proteo lytic processing of GH, which may become biologically inac tive (Komatsu et al, 2007). As we do not expect transgene expression in the pituitary gland and Lekti is still present in Tg KLK5, it is possible that other factors contribute to the growth delay in Tg KLK5 mice.…”

Section: Discussionmentioning

confidence: 99%

Transgenic kallikrein 5 mice reproduce major cutaneous and systemic hallmarks of Netherton syndrome

Furio¹,

Veer²,

Jaillet³

et al. 2014

J Cell Biol

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Section: Discussionmentioning

confidence: 99%

Transgenic kallikrein 5 mice reproduce major cutaneous and systemic hallmarks of Netherton syndrome

Furio¹,

Veer²,

Jaillet³

et al. 2014

J Cell Biol

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“…Several lines of data indicate that KLKs may also regulate the bioavailability of hormones and growth factors. For instance, several KLKs (KLKs 4 -6, 8, 13, and 14) were shown to cleave human growth hormone yielding to various inactive isoforms (15). Conversely, KLK3 was reported to activate latent TGF-␤ (16), and KLKs 1, 2, 3, 4, 11, and 14 were proposed to modify the bioavailability of insulin-like growth factors (IGFs) by fragmentation of IGF-binding proteins (IGFBP) (13,14).…”

mentioning

confidence: 99%

Kallikrein-related Peptidase 12 Hydrolyzes Matricellular Proteins of the CCN Family and Modifies Interactions of CCN1 and CCN5 with Growth Factors

Guillon-Munos

Οικονομοπούλου

Michel

et al. 2011

Journal of Biological Chemistry

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Kallikrein-related peptidases (KLKs) are an emerging group of secreted serine proteases involved in several physiological and pathological processes. We used a degradomic approach to identify potential substrates of KLK12. MDA-MB-231 cells were treated either with KLK12 or vehicle control, and the proteome of the overlying medium was analyzed by mass spectrometry. CCN1 (cyr61, ctgf, nov) was among the proteins released by the KLK12-treated cells, suggesting that KLK12 might be responsible for the shedding of this protein from the cell surface. Fragmentation of CCN1 by KLK12 was further confirmed in vitro, and the main cleavage site was localized in the hinge region between the first and second half of the recombinant protein. KLK12 can target all six members of the CCN family at different proteolytic sites. Limited proteolysis of CCNs (cyr61, ctgf, nov) was also observed in the presence of other members of the KLK family, such as KLK1, KLK5, and KLK14, whereas KLK6, KLK11, and KLK13 were unable to fragment CCNs. Because KLK12 seems to have a role in angiogenesis, we investigated the relations between KLK12, CCNs, and several factors known to be involved in angiogenesis. Solid phase binding assays showed that fragmentation of CCN1 or CCN5 by KLK12 prevents VEGF 165 binding, whereas it also triggers the release of intact VEGF and BMP2 from the CCN complexes. The KLK12-mediated release of TGF-␤1 and FGF-2, either as intact or truncated forms, was found to be concentration-dependent. These findings suggest that KLK12 may indirectly regulate the bioavailability and activity of several growth factors through processing of their CCN binding partners.

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“…A single specific cleavage to generate two contiguous fragments of 5 kDa (AA 1 -43 ) and 17 kDa (AA 44 -191 ) has been reported to yield significant amounts of these isoforms in circulation (Warner et al 1993;Lewis et al 1994Lewis et al , 2000Sinha and Jacobsen 1994;Lopez-Guajardo et al 1998). Another cleavage has been reported at the AA 134 -150 segment (Wroblewski et al 1993;Alam et al 1998;Ge et al 2007;Komatsu et al 2007), although the existence of the resulting fragments has not been confirmed as no specific assay is available. Different biological roles have been reported both for described isoforms and for distinct sequence segments.…”

Section: Introductionmentioning

confidence: 92%

“…Furthermore, minor constituents of the GH family are generated through alternative splicing (20 and 17.5 kDa), glycosylation (24 kDa), deamidation, homo-and hetero-oligomerisation (Baumann 1999;Lewis et al 2000;Ryther et al 2003). The 22 kDa GH isoform is known to be proteolitically processed in different tissues (Wroblewski et al 1993;Alam et al 1998;Ge et al 2007;Komatsu et al 2007), resulting in a number of isoforms with different biological activity. This fact suggested a pro-hormone role for the 22 kDa isoform (Sinha and Jacobsen 1994;Haro et al 1996;Rowlinson et al 1996).…”

Section: Introductionmentioning

confidence: 99%

Characterisation of the 5 kDa growth hormone isoform

et al. 2008

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Proteolytic processing of human growth hormone by multiple tissue kallikreins and regulation by the serine protease inhibitor Kazal-Type5 (SPINK5) protein

Cited by 33 publications

References 51 publications

Transgenic kallikrein 5 mice reproduce major cutaneous and systemic hallmarks of Netherton syndrome

Transgenic kallikrein 5 mice reproduce major cutaneous and systemic hallmarks of Netherton syndrome

Kallikrein-related Peptidase 12 Hydrolyzes Matricellular Proteins of the CCN Family and Modifies Interactions of CCN1 and CCN5 with Growth Factors

Characterisation of the 5 kDa growth hormone isoform

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