Structural and functional diversity of lysyl oxidase and the LOX-like proteins

Molnár, J.; Fong, Ksk; He, Qingping; Hayashi, Kazushi; Kim, Y.; Fong, Sheri F. T.; Fogelgren, Ben; Szauter, Kornélia Molnárné; Mink, Mátyás; Csiszár, Katalin

doi:10.1016/s1570-9639(03)00053-0

Cited by 218 publications

(194 citation statements)

References 15 publications

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“…All four of the LOX-like proteins have the potential to contribute to extracellular stromal stiffness and fibrosis. 36 However, there is evidence that LOXL2 more specifically has a role in migration and epithelial-mesenchymal transition in tumor cells. 37,38 However, the function of individual LOXlike proteins in HSCs is unknown.…”

Section: Discussionmentioning

confidence: 99%

Chronic administration of valproic acid inhibits activation of mouse hepatic stellate cellsin vitroandin vivo

et al. 2009

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Section: Discussionmentioning

confidence: 99%

Chronic administration of valproic acid inhibits activation of mouse hepatic stellate cellsin vitroandin vivo

et al. 2009

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“…Lysyl oxidase-like 2 (EC 1.4.3, LOXL2) 2 is one of five members of the lysyl oxidase family, which have a highly conserved catalytic region containing a copper binding domain as well as a quinone cofactor that is formed by highly conserved lysine and tyrosine residues (1,2). LOXL2 serves as an extracellular matrix metalloenzyme that can oxidatively deaminate the ⑀-amine group of specific lysine residues of collagen and elastin (3).…”

mentioning

confidence: 99%

“…This deaminated product then forms cross-links in fibrillar collagen and elastin (4). The amino-terminal region of the members of the lysyl oxidase family varies greatly and thus may impart distinct functions to these proteins in vivo (2). Four scavenger receptor cysteine-rich (SRCR) domains make up the aminoterminal catalytic domain of LOXL2.…”

mentioning

confidence: 99%

Modulation of Lysyl Oxidase-like 2 Enzymatic Activity by an Allosteric Antibody Inhibitor

Rodrı́guez¹,

Vaysberg²,

Mikels³

et al. 2010

Journal of Biological Chemistry

124

111

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In this report, we assessed the steady-state enzymatic activity of lysyl oxidase-like 2 (LOXL2) against the substrates 1,5-diaminopentane (DAP), spermine, and fibrillar type I collagen. We find that both DAP and spermine are capable of activating LOXL2 to the same extent and have similar Michaelis constants (K m ϳ 1 mM) and catalytic rates (k cat ϳ 0.02 s ؊1 ). We also show that LOXL2 is capable of being inhibited by a known suicide inhibitor of lysyl oxidase (LOX), ␤-aminopropionitrile, which we find is a potent inhibitor of LOXL2 activity. The modality of inhibition of ␤-aminopropionitrile was also examined and found to be competitive with respect to the substrates DAP and spermine. In addition, we identified an antibody inhibitor (AB0023) of LOXL2 enzymatic function and have found that the inhibition occurs in a non-competitive manner with respect to both spermine and DAP. The binding epitope of AB0023 was mapped to the scavenger receptor cysteine-rich domain four of human LOXL2. AB0023 binds to a region remote from the catalytic domain making AB0023 an allosteric inhibitor of LOXL2. This affords AB0023 several advantages, because it is specific for LOXL2 and inhibits the enzymatic function of LOXL2 in a noncompetitive manner thereby allowing inhibition of LOXL2 regardless of substrate concentration. These results suggest that antibody allosteric modulators of enzymatic function represent a novel drug development strategy and, in the context of LOXL2, suggest that inhibitors such as these might be useful therapeutics in oncology, fibrosis, and inflammation.

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“…For many years, LOX has been demonstrated that it has diverse functions including the ability regulating gene transcription, cell growth control, cell motility and migration and cell adhesions (7). LOX is encoded by the LOX gene located on chromosome 5 (5q23.3-31.2) and belongs to a copper dependent amine-oxidase family currently consisting of five members (LOX, LOX-like protein (LOXL) 1, LOXL2, LOXL3 and LOXL4) (6,(8)(9)(10)(11). Recent studies have shown that LOX family is related to tumor fibrosis, invasion and metastasis (10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

Association between lysyl oxidase and fibrotic focus in relation with inflammation in breast cancer

et al. 2017

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Abstract. We hypothesized that lysyl oxidase (LOX) contributes to the formation of fibrotic focus (FF) in association with inflammation and serves a significant role in breast carcinogenesis. In the present study, the association between the expression of LOX family members and FF with regards to with inflammation was analyzed, and the prognostic significance of LOX and FF in breast cancer was investigated. Immunohistochemical staining for LOX, LOX-like protein (LOXL) 1, LOXL2 and LOXL3 was performed in primary breast cancer tissues. The status of FF within the tumor was assessed, including size and grade. Levels of inflammatory markers, intratumoral and peritumoral lymphocyte infiltration were also evaluated. The clinicopathological characteristics were evaluated from the medical records of patients. In the present study, the expression of LOX family members was not associated with the presence of FF. FF was identified to be associated with intratumoral and peritumoral inflammation, tumor stage, larger tumor size, lymph node metastasis, high histologic grade, and p53 expression. LOX and LOXL3 were associated with intratumoral, and peritumoral inflammation. Furthermore, LOXL1 was associated with intratumoral inflammation and interleukin-4. In addition, LOX was associated with cluster of differentiation 8 + T cells. LOXL3 was associated with expression of ER and PR, and molecular subtype. In the survival analysis, overall survival time was statistically significantly longer in the FF-negative compared with that in the FF-positive group. In conclusion, it was demonstrated that FF and the expression of LOX family members were associated with inflammation in breast cancer. FF was associated with poor prognostic markers of breast cancer. Further studies are required to clarify the mechanisms underlying the association between the LOX family, FF and inflammation in breast cancer.

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Structural and functional diversity of lysyl oxidase and the LOX-like proteins

Cited by 218 publications

References 15 publications

Chronic administration of valproic acid inhibits activation of mouse hepatic stellate cellsin vitroandin vivo

Chronic administration of valproic acid inhibits activation of mouse hepatic stellate cellsin vitroandin vivo

Modulation of Lysyl Oxidase-like 2 Enzymatic Activity by an Allosteric Antibody Inhibitor

Association between lysyl oxidase and fibrotic focus in relation with inflammation in breast cancer

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