Molecule Information

General Information of the Molecule (ID: Mol04377)

• 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

  RTDM: Regulation by the Disease Microenvironment

Drug Resistance Data Categorized by Drug

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

Bortezomib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Disease Class: Multiple myeloma [ICD-11: 2A83.0] [1]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Resistant Drug: Bortezomib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: NCI-H929 cells; Bone marrow; Homo sapiens (Human); CVCL_1600
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: In particular, the dynamic interaction between BM mesenchymal stem cells (BM-MSC) and MM cells has shown great relevance. Here we showed that inhibiting both PKC and NF-kappaB signalling pathways in BM-MSC reduced cell survival in the MM cell line H929 and increased its susceptibility to the proteasome inhibitor bortezomib. PKC-mediated cell survival inhibition and bortezomib susceptibility induction were better performed by the chimeric peptide HKPS than by the classical enzastaurin inhibitor, probably due to its greatest ability to inhibit cell adhesion and its increased capability to counteract the NF-kappaB-related signalling molecules increased by the co-cultivation of BM-MSC with H929 cells. Thus, inhibiting two coupled signalling molecules in BM-MSC was more effective in blocking the supportive cues emerging from the mesenchymal stroma.

References

• Ref 1: Simultaneously Targeting Two Coupled Signalling Molecules in the Mesenchymal Stem Cell Support Efficiently Sensitises the Multiple Myeloma Cell Line H929 to Bortezomib. Int J Mol Sci. 2023 May 2;24(9):8157.