Molecule Information

General Information of the Molecule (ID: Mol00696)

• Name: Serine/threonine-protein kinase ULK1 (ULK1) ,Homo sapiens
• Synonyms: Autophagy-related protein 1 homolog; ATG1; hATG1; Unc-51-like kinase 1; KIAA0722
• Molecule Type: Protein
• Gene Name: ULK1
• Gene ID: 8408
• Location: chr12:131894622-131923150[+]
• Sequence:
  MEPGRGGTETVGKFEFSRKDLIGHGAFAVVFKGRHREKHDLEVAVKCINKKNLAKSQTLL
  GKEIKILKELKHENIVALYDFQEMANSVYLVMEYCNGGDLADYLHAMRTLSEDTIRLFLQ
  QIAGAMRLLHSKGIIHRDLKPQNILLSNPAGRRANPNSIRVKIADFGFARYLQSNMMAAT
  LCGSPMYMAPEVIMSQHYDGKADLWSIGTIVYQCLTGKAPFQASSPQDLRLFYEKNKTLV
  PTIPRETSAPLRQLLLALLQRNHKDRMDFDEFFHHPFLDASPSVRKSPPVPVPSYPSSGS
  GSSSSSSSTSHLASPPSLGEMQQLQKTLASPADTAGFLHSSRDSGGSKDSSCDTDDFVMV
  PAQFPGDLVAEAPSAKPPPDSLMCSGSSLVASAGLESHGRTPSPSPPCSSSPSPSGRAGP
  FSSSRCGASVPIPVPTQVQNYQRIERNLQSPTQFQTPRSSAIRRSGSTSPLGFARASPSP
  PAHAEHGGVLARKMSLGGGRPYTPSPQVGTIPERPGWSGTPSPQGAEMRGGRSPRPGSSA
  PEHSPRTSGLGCRLHSAPNLSDLHVVRPKLPKPPTDPLGAVFSPPQASPPQPSHGLQSCR
  NLRGSPKLPDFLQRNPLPPILGSPTKAVPSFDFPKTPSSQNLLALLARQGVVMTPPRNRT
  LPDLSEVGPFHGQPLGPGLRPGEDPKGPFGRSFSTSRLTDLLLKAAFGTQAPDPGSTESL
  QEKPMEIAPSAGFGGSLHPGARAGGTSSPSPVVFTVGSPPSGSTPPQGPRTRMFSAGPTG
  SASSSARHLVPGPCSEAPAPELPAPGHGCSFADPITANLEGAVTFEAPDLPEETLMEQEH
  TEILRGLRFTLLFVQHVLEIAALKGSASEAAGGPEYQLQESVVADQISLLSREWGFAEQL
  VLYLKVAELLSSGLQSAIDQIRAGKLCLSSTVKQVVRRLNELYKASVVSCQGLSLRLQRF
  FLDKQRLLDRIHSITAERLIFSHAVQMVQSAALDEMFQHREGCVPRYHKALLLLEGLQHM
  LSDQADIENVTKCKLCIERRLSALLTGICA
• Function: Serine/threonine-protein kinase involved in autophagy in response to starvation. Acts upstream of phosphatidylinositol 3-kinase PIK3C3 to regulate the formation of autophagophores, the precursors of autophagosomes. Part of regulatory feedback loops in autophagy: acts both as a downstream effector and negative regulator of mammalian target of rapamycin complex 1 (mTORC1) via interaction with RPTOR. Activated via phosphorylation by AMPK and also acts as a regulator of AMPK by mediating phosphorylation of AMPK subunits PRKAA1, PRKAB2 and PRKAG1, leading to negatively regulate AMPK activity. May phosphorylate ATG13/KIAA0652 and RPTOR; however such data need additional evidences. Plays a role early in neuronal differentiation and is required for granule cell axon formation. May also phosphorylate SESN2 and SQSTM1 to regulate autophagy. Phosphorylates FLCN, promoting autophagy. Phosphorylates AMBRA1 in response to autophagy induction, releasing AMBRA1 from the cytoskeletal docking site to induce autophagosome nucleation. Phosphorylates ATG4B, leading to inhibit autophagy by decreasing both proteolytic activation and delipidation activities of ATG4B.
• Uniprot ID: ULK1_HUMAN
• Ensembl ID: ENSG00000177169
• HGNC ID: HGNC:12558

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) 3 drug(s) in total

Crizotinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Non-small cell lung cancer [1]

• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Sensitive Drug: Crizotinib
• Molecule Alteration: Phosphorylation; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: ULk1 signaling pathway; Inhibition; hsa04211
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vivo Model: Nude mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; TUNEL assay; Flow cytometry assay
• Mechanism Description: Silencing of LncRNA-HOTAIR decreases drug resistance of Non-Small Cell Lung Cancer cells by inactivating autophagy via suppressing the phosphorylation of ULk1.

Dasatinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung cancer [2]

• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Sensitive Drug: Dasatinib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: miR106a/ULk1 signaling pathway; Inhibition; hsa05206
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Resazurin conversion assay
• Mechanism Description: Src inhibition results in autophagy activation in NSCLC cell lines. Combining Src with autophagy inhibition results in significant cell death. Induction of ULk1 upon Scr inhibition allows for autophagy activation. Src inhibition causes induction of the ULk1 targeting microRNA-106a. Expression of the "oncogenic" miR-106a sensitizes NSCLC cells to Src inhibition.

Doxorubicin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Hepatocellular carcinoma [3]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Sensitive Drug: Doxorubicin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR26a/b can promote apoptosis and sensitize HCC to chemotherapy via suppressing the expression of autophagy initiator ULk.

Disease Class: Breast cancer [4]

• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Sensitive Drug: Doxorubicin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; RIP assay; Luciferase reporter assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-489 acts as a therapeutic sensitizer in breast cancer cells by inhibiting doxorubicin-induced cytoprotective autophagy and directly targeting LAPTM4B.

Clinical Trial Drug(s) 1 drug(s) in total

Saracatinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung cancer [2]

• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Sensitive Drug: Saracatinib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: miR106a/ULk1 signaling pathway; Inhibition; hsa05206
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Resazurin conversion assay
• Mechanism Description: Src inhibition results in autophagy activation in NSCLC cell lines. Combining Src with autophagy inhibition results in significant cell death. Induction of ULk1 upon Scr inhibition allows for autophagy activation. Src inhibition causes induction of the ULk1 targeting microRNA-106a. Expression of the "oncogenic" miR-106a sensitizes NSCLC cells to Src inhibition.

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Liver cancer [ICD-11: 2C12]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Liver
• The Specified Disease: Liver cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.08E-01; Fold-change: -9.51E-02; Z-score: -2.15E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 7.07E-01; Fold-change: -1.05E-02; Z-score: -2.12E-02
• The Expression Level of Disease Section Compare with the Other Disease Section: p-value: 6.43E-01; Fold-change: -9.98E-02; Z-score: -2.64E-01

Lung cancer [ICD-11: 2C25]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Lung
• The Specified Disease: Lung cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.05E-21; Fold-change: 2.27E-01; Z-score: 8.11E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 5.31E-01; Fold-change: -1.82E-02; Z-score: -4.49E-02

Breast cancer [ICD-11: 2C60]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Breast tissue
• The Specified Disease: Breast cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.43E-41; Fold-change: 4.79E-01; Z-score: 1.03E+00
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 1.13E-03; Fold-change: 3.36E-01; Z-score: 6.02E-01

References

• Ref 1: Silencing of LncRNA-HOTAIR decreases drug resistance of Non-Small Cell Lung Cancer cells by inactivating autophagy via suppressing the phosphorylation of ULK1. Biochem Biophys Res Commun. 2018 Mar 18;497(4):1003-1010. doi: 10.1016/j.bbrc.2018.02.141. Epub 2018 Feb 19.
• Ref 2: MicroRNA-106a targets autophagy and enhances sensitivity of lung cancer cells to Src inhibitors. Lung Cancer. 2017 May;107:73-83. doi: 10.1016/j.lungcan.2016.06.004. Epub 2016 Jun 14.
• Ref 3: MiR-26 enhances chemosensitivity and promotes apoptosis of hepatocellular carcinoma cells through inhibiting autophagy. Cell Death Dis. 2017 Jan 12;8(1):e2540. doi: 10.1038/cddis.2016.461.
• Ref 4: Autophagy, Cell Viability, and Chemoresistance Are Regulated By miR-489 in Breast Cancer. Mol Cancer Res. 2018 Sep;16(9):1348-1360. doi: 10.1158/1541-7786.MCR-17-0634. Epub 2018 May 21.