Search results for LOR

Showing 13 results out of 13

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Protein (2 results from a total of 2)

Identifier: R-HSA-8847711
Species: Homo sapiens
Compartment: cornified envelope
Primary external reference: UniProt: LORICRIN: P23490
Identifier: R-HSA-6810848
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: LORICRIN: P23490

Interactor (1 results from a total of 1)

Identifier: Q9UN81
Species: Homo sapiens
Primary external reference: UniProt: Q9UN81

Reaction (3 results from a total of 3)

Identifier: R-HSA-9715355
Species: Homo sapiens
Compartment: cytosol, plasma membrane
The following ALK mutants are resistant to inhibition by lorlatinib:

ALK I1171N: Ouseph et al, 2019
ALK I1171S: Takahashi et al, 2020
ALK L1196M: Yoda et al, 2018
ALK L1198F: Yoda et al, 2018
ALK G1202R: Kougioumtzi et al, 2019
ALK G1269A: Kougioumtzi et al, 2019; Takahashi et al, 2020; Yoda et al, 2018
Identifier: R-HSA-6811539
Species: Homo sapiens
Compartment: cytosol, plasma membrane
The inital scaffold of the cornified envelope (CE) is reinforced by the inclusion of loricrin (LOR) and small proline-rich proteins (SPRs), which together comprise about 75% of the total mass of the CE. Other proteins include filaggrin (FLG) (8%), elafin (6%), cystatin A (5%), involucrin (IVL) and keratin intermediate filaments (KIFs) (about 2% each) (Steinert & Marekov 1995). Other minor proteins include repetin (RPTN), trichohyalin (TCHH) and elafin (PI3) (Steinert & Marekov 1997, Steinert et al. 1998).

LOR is poorly soluble in vivo, while SPRs are very soluble. Both are preferred substrates of cytosolic transglutaminase-3 (TGM3) (Candi et al. 1999, Steinert et al. 1999, Tarcsa et al. 1999), which suggests that TGM3 may cross-link LOR and SPRs to create soluble complexes that are more easily translocated to the cell periphery (Kalinin et al. 2002). These cross-linked oligomers are good substrates for TGM1 (Candi et al. 1999, Steinert et al. 1999) which may link the LOR-SPR complexes to the CE scaffold. LOR can also be crosslinked by TGM5 (Candi et al. 2001). SPR content varies in epithelia from different body sites and increasing SPR content correlates with mechanical requirements of the tissue (Steinert et al. 1998). In humans LOR is initially deposited in the granular layer of the epidermis in keratohyalin granules, intermixed with profilaggrin (Yoneda & Steinert 1993). These are encoded in a linked 'Epidermal Differentiation Complex.' (Kypriotou et al. 2012, Niehues et al. 2016).

As the main component of the CE (Steinert & Marekov 1995), LOR is thought to function as the main reinforcement protein. LOR proteins are extensively crosslinked through isopeptide bonds but also crosslinked to SPRs, which may function as bridging proteins between LOR molecules (Candi et al. 2005). LOR can also form crosslinks with keratin and filaggrin (Steinert & Marekov 1995). CE crosslinking involves TGM1, TGM3 and TGM5 (Lorand & Graham 2003). The type-II keratin chains (K1, K2e and K5) are crosslinked at a specific Lys residue that is located in a conserved region of the V1 subdomain of the head domain (Steinert & Marekov 1995). IVL can be crosslinked by TGM1, which preferentially crosslinks Gln495 and Gln496 (Simon & Green 1998). In vitro, LOR is a substrate for TGM1-3 and 5 (Candi et al. 1995). In the epidermis, TGM1, TGM5 and TGM3 are believed to crosslink LOR sequentially; an initial attachment by TGM1 and 5 forms interchain crosslinks followed by a compaction process that involves TGM3 (Candi et al. 2005). SPRs are also TGM substrates, particularly TGM3 (Candi et al. 1999, Tarcsa et al. 1998, Steinert et al. 1999).

FLG binds KIFs, aggregating them into tight bundles. As a component of the CE, FLG 'glues' KIFs to the CE and coordinates the structure of cornifying cells (Steinert & Marekov 1995, Candi et al. 2005).
Identifier: R-HSA-6810894
Species: Homo sapiens
Compartment: plasma membrane, cytosol
The current model of cornified envelope (CE) formation suggests that crosslinking between envoplakin (EVPL), periplakin (PPL), involucrin (IVL) and small proline-rich proteins (SPRs) results in the formation of a layer along the entire inner surface of the plasma membrane, including desmosomes, forming a scaffold to which other precursors are added to form the mature CE (Steinert & Marekov 1999, Kalinin et al. 2002, Candi et al. 2001).

Transglutaminases (TGs) are believed to mediate the intramolecular bonds involved in CE formation. They catalyze inter-protein bond formation by forming a thiolester acyl-enzyme intermediate and subsequently transferring the acyl residue to a primary amine (Folk & Finlayson 1977, Folk 1980). The amine acceptor is generally provided by the epsilon-amino group of a protein-bound lysine and the link formed is an N6-(gamma-glutamyl)lysine isopeptide bond.

CE assembly is thought to be initiated on the inner face of the plasma membrane between desmosomes by the cross-linking of involucrin to itself, to envoplakin and perhaps to periplakin (Steinert & Marekov 1999). The extent of homo- and heterologous cross-linking varies as the CE matures. In the immature CE, EVPL, IVL, SPR1, and SPR2 are largely cross-linked to themselves; EVPL-IVL and IVL-SPR crosslinks are common while cross-links between desmoplakin (DSP) and IVL or DSP and EVPL are not. Later there are many more cross-links between DSP and IVL, DSP and EVL, or IVL and type II keratins. Loricrin (LOR) cross-linking to other protein partners appears later.

Transglutaminase-1 (TGM1) can crosslink IVL (Simon & Green 1988, Nemes et al. 1999), LOR (Candi et al. 2001), SPR3 (Steinert et al. 1999) and is thought to be responsible for EVPL crosslinking to itself and to IVL (Steinert & Marekov 1999). TGM5 can catalyse homo-crosslinking in LOR, SPR1, SPR2, and IVL, and hetero-crosslinks between LOR-SPR3 (Candi et al. 2001).

Drug (2 results from a total of 2)

Identifier: R-ALL-9692531
Compartment: extracellular region
Primary external reference: Guide to Pharmacology: loratadine: 7216
Identifier: R-ALL-9702126
Compartment: cytosol
Primary external reference: Guide to Pharmacology: lorlatinib: 7476

Set (1 results from a total of 1)

Identifier: R-HSA-9714053
Species: Homo sapiens
Compartment: plasma membrane

Pathway (1 results from a total of 1)

Identifier: R-HSA-9717329
Species: Homo sapiens
Compartment: cytosol, plasma membrane
Lorlatinib is a third generation tyrosine kinase inhibitor with effectiveness against ALK and ROS rearranged cancers. This pathway describes ALK mutants that are resistant to inhibition by lorlatinib (Yoda et al, 2018; Takahashi et al, 2020; reviewed in Della Corte et al, 2018; Lin et al, 2017; Facchinietti et al, 2016).

Person (2 results from a total of 2)

Authored Pathways: 12
Reviewed Pathways: 1
Authored Reactions: 33
Reviewed Reactions: 0
Authored Pathways: 0
Reviewed Pathways: 8
Authored Reactions: 0
Reviewed Reactions: 53

Icon (1 results from a total of 1)

Species: Homo sapiens
Curator: Karen Rothfels
Designer: Cristoffer Sevilla
LORLATINIB icon
Lorlatinib (PF-06463922) is a kinase inhibitor with action on ALK and ROS1 proto-oncogenes. It is a reversible, ATP-competitive small molecule inhibitor. Lorlatinib is a third generation ALK inhibitor designed to have improved blood-brain barrier penetrance compared to older second generation ALK inhibitors such as the approved drugs ceritinib, alectinib, and brigatinib, with the aim of better targeting metastatic NSCLC lesions in the brain. Advanced generation ALK inhibitors are those which target acquired ALK mutations resistant to the original first generation inhibitor crizotinib, which occur in virtually all AKL-rearranged NSCLC tumours within a year of starting crizotinib therapy. In fact, the cyano group of lortatinib is highly selective for the ALK mutation L1196M.
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