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2.A.1.13.6
Plasma membrane proton-linked monocarboxylate transporter, MCT4 or MCT-4 (SLC16A3). It catalyzes the rapid low affinity plasma membrane transport of many monocarboxylates such as lactate, pyruvate, branched-chain oxo acids derived from leucine, valine and isoleucine, and the ketone bodies acetoacetate, beta-hydroxybutyrate and acetate.  It is the main transporter that catalyzes lactate efflux from glycolyzing cells (Halestrap 2013; Papakonstantinou et al. 2021).  Residues binding high affinity inhibitors have been identified (Nancolas et al. 2015).  It forms a complex with binding partner, CD147/BSG, which regulates the transport activity (Fisel et al. 2015). It plays a role in aggressive breast cancer subtypes (Li et al. 2018) as well as other cancers (Park et al. 2018).  MCT4 may be a therapeutic target for colorectal cancer (Kim et al. 2018). MCTs 1 and 4 are present in increased amounts in solid tumors, and inhibitors are potential therapeutics (Puri and Juvale 2020). Anagliptin promotes apoptosis in mouse colon carcinoma cells via MCT-4/lactate-mediated intracellular acidosis (Li et al. 2022). Dietary folate deficiency promotes lactate metabolic disorders that sensitize lung cancer metastasis through mTOR-signaling-mediated targets (Chen et al. 2023). Shikonin reduced MCT4 expression and activation, resulting in inhibition of aerobic glycolysis in cancer-associated fibroblasts (CAFs) and overcoming CAF-induced gemcitabine resistance in pancreatic cancer (PC). Shikonin is a promising chemosensitizing phytochemical agent when used in combination with gemcitabine for PC treatment. The results suggest that disrupting the metabolic coupling between cancer cells and stromal cells might provide an attractive strategy for improving gemcitabine efficacy (Hu et al. 2024).  Sulforaphane (SFN)  inhibits non-small cell lung cancer (NSCLC) growth and metastasis by reducing lactate production by regulating the expressions of monocarboxylate transporter 1 (MCT1) and MCT4 that transport lactate across cell membrane (Shi et al. 2024).

Accession Number:O15427
Protein Name:Monocarboxylate transporter 4
Length:465
Molecular Weight:49469.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:12
Location1 / Topology2 / Orientation3: Cell membrane1 / Multi-pass membrane protein2
Substrate monocarboxylic acid anion, acetate, lactate, lactate, pyruvate

Cross database links:

RefSeq: NP_001035887.1    NP_001035888.1    NP_004198.1   
Entrez Gene ID: 9123   
Pfam: PF07690   
OMIM: 603877  gene
KEGG: hsa:9123    hsa:9123   

Gene Ontology

GO:0005887 C:integral to plasma membrane
GO:0005624 C:membrane fraction
GO:0015355 F:secondary active monocarboxylate transmembr...
GO:0015293 F:symporter activity
GO:0015718 P:monocarboxylic acid transport
GO:0015711 P:organic anion transport
GO:0055085 P:transmembrane transport
GO:0015629 C:actin cytoskeleton
GO:0031965 C:nuclear membrane
GO:0008028 F:monocarboxylic acid transmembrane transporter activity
GO:0015355 F:secondary active monocarboxylate transmembrane transporter activity
GO:0007596 P:blood coagulation
GO:0050900 P:leukocyte migration
GO:0006090 P:pyruvate metabolic process

References (12)

[1] “Cloning and sequencing of four new mammalian monocarboxylate transporter (MCT) homologues confirms the existence of a transporter family with an ancient past.”  Price N.T.et.al.   9425115
[2] “Complete sequencing and characterization of 21,243 full-length human cDNAs.”  Ota T.et.al.   14702039
[3] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project Teamet.al.   15489334
[4] “Global, in vivo, and site-specific phosphorylation dynamics in signaling networks.”  Olsen J.V.et.al.   17081983
[5] “Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle.”  Daub H.et.al.   18691976
[6] “A quantitative atlas of mitotic phosphorylation.”  Dephoure N.et.al.   18669648
[7] “Cloning and sequencing of four new mammalian monocarboxylate transporter (MCT) homologues confirms the existence of a transporter family with an ancient past.”  Price N.T.et.al.   9425115
[8] “Complete sequencing and characterization of 21,243 full-length human cDNAs.”  Ota T.et.al.   14702039
[9] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project Teamet.al.   15489334
[10] “Global, in vivo, and site-specific phosphorylation dynamics in signaling networks.”  Olsen J.V.et.al.   17081983
[11] “Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle.”  Daub H.et.al.   18691976
[12] “A quantitative atlas of mitotic phosphorylation.”  Dephoure N.et.al.   18669648

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FASTA formatted sequence 
1:	MGGAVVDEGP TGVKAPDGGW GWAVLFGCFV ITGFSYAFPK AVSVFFKELI QEFGIGYSDT 
61:	AWISSILLAM LYGTGPLCSV CVNRFGCRPV MLVGGLFASL GMVAASFCRS IIQVYLTTGV 
121:	ITGLGLALNF QPSLIMLNRY FSKRRPMANG LAAAGSPVFL CALSPLGQLL QDRYGWRGGF 
181:	LILGGLLLNC CVCAALMRPL VVTAQPGSGP PRPSRRLLDL SVFRDRGFVL YAVAASVMVL 
241:	GLFVPPVFVV SYAKDLGVPD TKAAFLLTIL GFIDIFARPA AGFVAGLGKV RPYSVYLFSF 
301:	SMFFNGLADL AGSTAGDYGG LVVFCIFFGI SYGMVGALQF EVLMAIVGTH KFSSAIGLVL 
361:	LMEAVAVLVG PPSGGKLLDA THVYMYVFIL AGAEVLTSSL ILLLGNFFCI RKKPKEPQPE 
421:	VAAAEEEKLH KPPADSGVDL REVEHFLKAE PEKNGEVVHT PETSV