Molecule Information

General Information of the Molecule (ID: Mol04425)

• Name: Dual specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2) ,Homo sapiens
• Molecule Type: Protein
• Gene Name: DYRK2
• Gene ID: 8445
• Sequence:
  MLTRKPSAAAPAAYPTGRGGDSAVRQLQASPGLGAGATRSGVGTGPPSPIALPPLRASNA
  AAAAHTIGGSKHTMNDHLHVGSHAHGQIQVQQLFEDNSNKRTVLTTQPNGLTTVGKTGL
  P VVPERQLDSIHRRQGSSTSLKSMEGMGKVKATPMTPEQAMKQYMQKLTAFEHHEIFSY
  PE IYFLGLNAKKRQGMTGGPNNGGYDDDQGSYVQVPHDHVAYRYEVLKVIGKGSFGQVV
  KAY DHKVHQHVALKMVRNEKRFHRQAAEEIRILEHLRKQDKDNTMNVIHMLENFTFRNH
  ICMT FELLSMNLYELIKKNKFQGFSLPLVRKFAHSILQCLDALHKNRIIHCDLKPENIL
  LKQQG RSGIKVIDFGSSCYEHQRVYTYIQSRFYRAPEVILGARYGMPIDMWSLGCILAE
  LLTGYP LLPGEDEGDQLACMIELLGMPSQKLLDASKRAKNFVSSKGYPRYCTVTTLSDG
  SVVLNGG RSRRGKLRGPPESREWGNALKGCDDPLFLDFLKQCLEWDPAVRMTPGQALRH
  PWLRRRLP KPPTGEKTSVKRITESTGAITSISKLPPPSSSASKLRTNLAQMTDANGNIQ
  QRTVLPKLV S
• Function: Serine/threonine-protein kinase involved in the regulation ofthe mitotic cell cycle, cell proliferation, apoptosis, organization ofthe cytoskeleton and neurite outgrowth. Functions in part via its rolein ubiquitin-dependent proteasomal protein degradation. Functionsdownstream of ATM and phosphorylates p53/TP53 at 'Ser-46', and therebycontributes to the induction of apoptosis in response to DNA damage.Phosphorylates NFATC1, and thereby inhibits its accumulation in thenucleus and its transcription factor activity. Phosphorylates EIF2B5 at'Ser-544', enabling its subsequent phosphorylation and inhibition byGSK3B. Likewise, phosphorylation of NFATC1, CRMP2/DPYSL2 andCRMP4/DPYSL3 promotes their subsequent phosphorylation by GSK3B. Mayplay a general role in the priming of GSK3 substrates. Inactivates GYS1by phosphorylation at 'Ser-641', and potentially also a secondphosphorylation site, thus regulating glycogen synthesis. Mediates EDVPE3 ligase complex formation and is required for the phosphorylation andsubsequent degradation of KATNA1. Phosphorylates TERT at 'Ser-457',promoting TERT ubiquitination by the EDVP complex. PhosphorylatesSIAH2, and thereby increases its ubiquitin ligase activity. Promotesthe proteasomal degradation of MYC and JUN, and thereby regulatesprogress through the mitotic cell cycle and cell proliferation.Promotes proteasomal degradation of GLI2 and GLI3, and thereby plays arole in smoothened and sonic hedgehog signaling. Plays a role incytoskeleton organization and neurite outgrowth via its phosphorylationof DCX and DPYSL2. Phosphorylates CRMP2/DPYSL2, CRMP4/DPYSL3, DCX,EIF2B5, EIF4EBP1, GLI2, GLI3, GYS1, JUN, MDM2, MYC, NFATC1, p53/TP53,TAU/MAPT and KATNA1. Can phosphorylate histone H1, histone H3 andhistone H2B . Can phosphorylate CARHSP1 .{ECO:0000269|PubMed:11311121, ECO:0000269|PubMed:12588975,ECO:0000269|PubMed:14593110, ECO:0000269|PubMed:15910284,ECO:0000269|PubMed:16511445, ECO:0000269|PubMed:16611631,ECO:0000269|PubMed:17349958, ECO:0000269|PubMed:18455992,ECO:0000269|PubMed:18599021, ECO:0000269|PubMed:19287380,ECO:0000269|PubMed:22307329, ECO:0000269|PubMed:22878263,ECO:0000269|PubMed:23362280, ECO:0000269|PubMed:9748265}.
• Uniprot ID: DYRK2_HUMAN
• Ensembl ID: ENSG0000012733411
• HGNC ID: HGNC:3093

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

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

Docetaxel

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast adenocarcinoma [ICD-11: 2C60.1] [1]

• Resistant Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF7-Doc cells; Breast; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: RT-PCR; Immunofluorescence staining assay
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric assay
• Mechanism Description: Docetaxel-resistant cells exhibited down-regulated DYRK2 and up-regulated Twist1 expression. DYRK2 overexpression reversed drug resistance, decreased migration, and attenuated Twist1 and GST-pi expression. DYRK2 was found to suppress Twist1 expression through ubiquitination, supported by decreased Twist1 phosphorylation and increased ubiquitination after DYRK2 overexpression. Twist1 overexpression counteracted DYRK2-induced drug sensitivity enhancement, promoting GST-pi expression, EMT, migration, and proliferation. Twist1 was shown to bind to the GSTP1 promoter, enhancing its transcription. In vivo experiments confirmed DYRK2's ability to suppress chemoresistance in breast cancer cells.

Disease Class: Breast adenocarcinoma [ICD-11: 2C60.1] [1]

• Resistant Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF7-Doc 2ug cells; Breast; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: RT-PCR; Immunofluorescence staining assay
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric assay
• Mechanism Description: Docetaxel-resistant cells exhibited down-regulated DYRK2 and up-regulated Twist1 expression. DYRK2 overexpression reversed drug resistance, decreased migration, and attenuated Twist1 and GST-pi expression. DYRK2 was found to suppress Twist1 expression through ubiquitination, supported by decreased Twist1 phosphorylation and increased ubiquitination after DYRK2 overexpression. Twist1 overexpression counteracted DYRK2-induced drug sensitivity enhancement, promoting GST-pi expression, EMT, migration, and proliferation. Twist1 was shown to bind to the GSTP1 promoter, enhancing its transcription. In vivo experiments confirmed DYRK2's ability to suppress chemoresistance in breast cancer cells.

References

• Ref 1: DYRK2 controls GSTPI expression through ubiquitination and degradation of Twist1 to reduce chemotherapy resistance caused by EMT in breast cancer. J Mol Histol. 2024 Dec 6;56(1):35.