Molecule Information

General Information of the Molecule (ID: Mol04378)

• Name: Interleukin-1 receptor-associated kinase 1 (IRAK1) ,Homo sapiens
• Molecule Type: Protein
• Gene Name: IRAK1
• Gene ID: 3654
• Sequence:
  MAGGPGPGEPAAPGAQHFLYEVPPWVMCRFYKVMDALEPADWCQFAALIVRDQTELRLCE
  RSGQRTASVLWPWINRNARVADLVHILTHLQLLRARDIITAWHPPAPLPSPGTTAPRPS
  S IPAPAEAEAWSPRKLPSSASTFLSPAFPGSQTHSGPELGLVPSPASLWPPPPSPAPSS
  TK PGPESSVSLLQGARPFPFCWPLCEISRGTHNFSEELKIGEGGFGCVYRAVMRNTVYA
  VKR LKENADLEWTAVKQSFLTEVEQLSRFRHPNIVDFAGYCAQNGFYCLVYGFLPNGSL
  EDRL HCQTQACPPLSWPQRLDILLGTARAIQFLHQDSPSLIHGDIKSSNVLLDERLTPK
  LGDFG LARFSRFAGSSPSQSSMVARTQTVRGTLAYLPEEYIKTGRLAVDTDTFSFGVVV
  LETLAG QRAVKTHGARTKYLKDLVEEEAEEAGVALRSTQSTLQAGLAADAWAAPIAMQI
  YKKHLDP RPGPCPPELGLGLGQLACCCLHRRAKRRPPMTQVYERLEKLQAVVAGVPGHS
  EAASCIPP SPQENSYVSSTGRAHSGAAPWQPLAAPSGASAQAAEQLQRGPNQPVESDES
  LGGLSAALR SWHLTPSCPLDPAPLREAGCPQGDTAGESSWGSGPGSRPTAVEGLALGSS
  ASSSSEPPQI IINPARQKMVQKLALYEDGALDSLQLLSSSSLPGLGLEQDRQGPEESDE
  FQS
• Function: Serine/threonine-protein kinase that plays a critical role ininitiating innate immune response against foreign pathogens. Involvedin Toll-like receptor and IL-1R signaling pathways. Is rapidlyrecruited by MYD88 to the receptor-signaling complex upon TLRactivation. Association with MYD88 leads to IRAK1 phosphorylation byIRAK4 and subsequent autophosphorylation and kinase activation.Phosphorylates E3 ubiquitin ligases Pellino proteins to promote pellino-mediated polyubiquitination of IRAK1. Then,the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinatedIRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and theNEMO-IKKA-IKKB complex. In turn, MAP3K7/TAK1 activates IKKs leading to NF-kappa-B nuclear translocation andactivation. Alternatively, phosphorylates TIRAP to promote itsubiquitination and subsequent degradation. Phosphorylates theinterferon regulatory factor 7 to induce its activation andtranslocation to the nucleus, resulting in transcriptional activationof type I IFN genes, which drive the cell in an antiviral state. Whensumoylated, translocates to the nucleus and phosphorylates STAT3.{ECO:0000269|PubMed:11397809, ECO:0000269|PubMed:12860405,ECO:0000269|PubMed:14684752, ECO:0000269|PubMed:15084582,ECO:0000269|PubMed:15465816, ECO:0000269|PubMed:15767370,ECO:0000269|PubMed:17997719, ECO:0000269|PubMed:20400509}.
• Uniprot ID: IRAK1_HUMAN
• Ensembl ID: ENSG0000018421615
• HGNC ID: HGNC:6112

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Investigative Drug(s) 1 drug(s) in total

IRAK-1 and -4 dual inhibitor

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Laryngeal carcinoma [ICD-11: 2C23.2] [1]

• Sensitive Disease: Laryngeal carcinoma [ICD-11: 2C23.2]
• Sensitive Drug: IRAK-1 and -4 dual inhibitor
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: IRAK-1 and-4 signaling pathway; Regulation; N.A.
• In Vitro Model: HEp-2 cells; Skin; Homo sapiens (Human); CVCL_1906
• Experiment for Molecule Alteration: Gene expression profiling assay; Flow cytometry; Western blot assay; ELISA assay
• Experiment for Drug Resistance: Drug sensitivity assay
• Mechanism Description: In this study, we investigated the role of Interleukin-1 receptor-associated kinases (IRAK) mediated Toll-like receptor (TLR)-signaling in chemo-resistance using a cell line-based in-vitro TPF-resistant HNSCC model of laryngeal origin. TPF chemo-resistant state showed over-expression and phosphorylation of the active downstream kinases IRAK-1 and IRAK-4 along with enhanced proliferative potential, survival, stemness and metastatic capability as compared to the parent cell line. Pharmacological inhibition of IRAK-1 and -4 had a cytostatic effect on chemo-resistant cells and re-sensitized them to chemotherapy. The treatment also decreased the pro-oncogenic effects of the chemo-resistant cells. Our study provides insights into the pro-oncogenic role of amplified IRAK-1 and-4 mediated TLR signaling in TPF-resistant HNSCC. Pharmacological inhibition of IRAK-1 and-4 signaling is a promising therapeutic strategy for TPF-resistant HNSCC. It can also be used as a combination therapy or a chemo-drug sparing regimen in HNSCC.

References

• Ref 1: Suppression of TLR signaling by IRAK-1 and -4 dual inhibitor decreases TPF-resistance-induced pro-oncogenic effects in HNSCC. 3 Biotech. 2023 Jan;13(1):14.