Table 1.
Oncoproteins, oncosuppressor proteins and autophagy
| Protein | Function(s) | Link(s) to cancer | Link(s) to autophagy | Reference |
|---|---|---|---|---|
| Oncoproteins | ||||
| AKT1 | Serine/threonine kinase | Hyperactivated or overexpressed in various neoplasms | Inhibits BECN1 and activates MTORCI | Carpten et al (2007); Laplante & Sabatini (2012); Wang et al (2012a); Huang et al (2013) |
| Stimulates autophagy via XIAP | ||||
| BCL2 | Anti-apoptotic Bcl-2 family members | Overexpressed in various hematological and solid tumors | Sequester BECN1 in inactive complexes | Pattingre et al (2005); Maiuri et al (2007b); Kang & Reynolds (2009); Anderson et al (2014); Wu et al (2014) |
| BCL-XL | BCL-XL inhibits mitophagy mediated by FUNDC1 | |||
| BRAF | Serine/threonine kinase | Mutated in melanoma and various histiocytoses | Activates MTORCI via ERK\TSC2\RHEB signaling | Davies et al (2002); Sharma et al (2006); Berres et al (2014); Corazzari et al (2014); Hervier et al (2014); Ma et al (2014) |
| BRAF hyperactivation promotes ER stress, in turn triggering autophagy | ||||
| E6 | E3 ubiquitin ligase | Etiological factor inHPV-associated cancers | Inhibits TP53 | Hanning et al (2013); de Freitas et al (2014); Hock & Vousden (2014) |
| E7 | RB1 inhibitor | Etiological factor in HPV-associated cancers | Suppresses autophagy, perhaps as a result of RB1 inhibition | Jiang et al (2010); Hanning et al (2013); de Freitas et al (2014) |
| HIF-1 | Transcription factor | Overexpressed in various tumors | Promotes mitophagy by transactivating BNIP3 and BNIP3L | Tracy et al (2007); Zhang et al (2008); Bellot et al (2009); Luo et al (2009); Wilkinson et al (2009) |
| HRAS | KRAS | Small GTP-binding proteins | Hyperactivated or overexpressed in various neoplasms | Furuta et al (2004); Shaw & Cantley (2006); Wei et al (2008); DeNicola et al (2011); Laplante & Sabatini (2012) |
| NRAS | Activate MTORCI via PI3K signaling | |||
| Derepress BECN1 upon the JNK1-mediated phosphorylation of BCL2 | ||||
| Promote the NRF2-dependent synthesis of p62 and NDP52 | ||||
| MDM2 | E3 ubiquitin ligase | Overexpressed in various neoplasms | Inhibits TP53 | Oliner et al (1992); Hock & Vousden (2014) |
| MYC | Transcription factors | Hyperactivated or overexpressed in various neoplasms | Inhibit autophagy upon 4EBP1 expression | Dalla-Favera et al (1982); Balakumaran et al (2009); Dang (2012); Toh et al (2013); Conacci-Sorrell et al (2014) |
| MYCL | Transactivate MAPK8, coding for the BECN1 derepressor JNK1 | |||
| MYCN | Truncated MYC promotes autophagy independent of transcription | |||
| MYC hyperactivation promotes ER stress, in turn triggering autophagy | ||||
| PDPK1 | Serine/threonine kinase | Hyperactivated in colorectal neoplasms | Activates MTORCI via AKT1\TSC2\RHEB signaling | Laplante & Sabatini (2012); Chinen et al (2014) |
| PI3K | Lipid kinase | Hyperactivated in various neoplasms | Activates MTORCI via AKT1\TSC2\RHEB signaling | Shayesteh et al (1999); Ma et al (2000); Laplante & Sabatini (2012) |
| RHEB | Small GTP-binding protein | Overexpressed in prostate carcinoma | Activates MTORCI | Inoki et al (2003); Nardella et al (2008) |
| RTKs | Tyrosine kinases | Hyperactivated or overexpressed in various neoplasms | Activate MTORCI via PI3K signaling | Slamon et al (1987); Paez et al (2004); Stephens et al (2004); Laplante & Sabatini (2012); Wei et al (2013); Lozy et al (2014) |
| EGFR phosphorylates BECN1, hence inactivating it | ||||
| SRC | Non-receptor tyrosine kinase | Hyperactivated in various cancers | Activates MTORCI via PI3K signaling | Irby et al (1999); Sen & Johnson (2011); Liu et al (2012b) |
| Phosphorylates FUNDC1, hence inactivating it | ||||
| XIAP | E3 ubiquitin ligase | Overexpressed in various tumors | Inhibits the autophagy-blocking activity of cytoplasmic TP53 (?) | Schimmer et al (2006); Huang et al (2013) |
| Oncosuppressor proteins | ||||
| AMBRA1 | Component of class III PI3K complex | Mutated in endometrial, colorectal and urinary tract neoplasms | Key factor for canonical autophagy | Codogno et al (2012); Cianfanelli et al (2015) |
| ATG5 | E3 ubiquitin ligase | Downregulated in melanoma | Key factor for canonical autophagy | Codogno et al (2012); Liu et al (2013a) |
| BECN1 | Component of class III PI3K complex | Monoallelically deleted or downregulated in various solid tumors | Key factor for canonical autophagy | Liang et al (1999); Qu et al (2003); Miracco et al (2007); Codogno et al (2012); Laddha et al (2014) |
| BH3-only proteins | Pro-apoptotic Bcl-2 family members | Downregulated in various hematological and solid tumors | Derepress BECN1 by displacing it from BCL2 and BCL-XL | Ahn et al (2007); Maiuri et al (2007a); Maiuri et al (2007b) |
| BIF1 | Component of class III PI3K complex | Downregulated in colorectal carcinoma | UVRAG interactor | Takahashi et al (2007); Coppola et al (2008); Takahashi et al (2013) |
| DAPK1 | Serine/threonine kinase | Downregulated in various solid tumors | Derepresses BECN1 by displacing it from BCL2 | Raveh et al (2001); Martoriati et al (2005); Christoph et al (2007); Zalckvar et al (2009) |
| Boosts a potentially self-amplifying p19ARF\TP53 response | ||||
| DIRAS3 | GTP-binding protein | Downregulated in breast and ovarian carcinoma | Inhibits MTORCI by antagonizing PI3K signaling | Yu et al (1999); Feng et al (2008); Lu et al (2008) |
| DRAM1 | Lysosomal protein | Downregulated in many tumors as a result of TP53 inactivation | Involved in TP53-dependent autophagy | Crighton et al (2006); Leroy et al (2014) |
| FIP200 | Multifunctional protein | Affected by truncating mutations in breast cancer | Component of the ULK1-ATG13-ATG101 complex | Chano et al (2002); Hara et al (2008) |
| FOXO1 | Transcription factor | Mutated in DLBCL | Interacts with ATG7 in the course of stress-induced autophagy | Huang et al (2005); Zhao et al (2010) |
| LKB1 | Serine/threonine kinase | Germline mutations cause Peutz–Jeghers's syndrome | Activates the TSC complex via AMPK | Hemminki et al (1998); Shaw et al (2004); Ji et al (2007) |
| Mutated in a proportion of SCCs and lung carcinomas | ||||
| NF1 | GTPase | Germline mutations cause type I neurofibromatosis | Activates the TSC complex by antagonizing RAS signaling | Fountain et al (1989); Xu et al (1990); Johannessen et al (2005) |
| RB1 | Transcription factor | Germline mutations cause hereditary retinoblastoma | Stimulates autophagy, perhaps upon BCL2 downregulation and consequent BECN1 derepression | Friend et al (1986); Cryns et al (1994); Gomez-Manzano et al (2001); Jiang et al (2010) |
| Mutated in various solid tumors | ||||
| p19ARF | MDM2 inhibitor | Mutated or deleted in several hematological and solid tumor | Stimulates autophagy via TP53-dependent and -independent mechanisms | Faderl et al (1999); Abida & Gu (2008); Pimkina et al (2009) |
| PTEN | Lipid phosphatase | Germline mutations cause the so-called PHTS | Inhibits MTORCI by antagonizing PI3K signaling | Liaw et al (1997); Marsh et al (1997); Arico et al (2001); Sansal & Sellers (2004) |
| Sporadically mutated in a large fraction of neoplasms | ||||
| smARF | Alternative CDKN2A product | Mutated or deleted in several hematological and solid tumors | Derepresses BECN1 by displacing it from BCL-XL | Faderl et al (1999); Reef et al (2006); Pimkina et al (2009) |
| TP53 | Transcription factor | Germline mutations cause the Li–Fraumeni syndrome | In physiological conditions, inhibits autophagy via non-transcriptional, cytoplasmic mechanisms | Malkin et al (1990); Moll et al (2005); Riley et al (2008); Maiuri et al (2010); Pietrocola et al (2013); Leroy et al (2014); McBride et al (2014) |
| Mutated or inactivated in > 50% of human malignancies | In response to stress, transactivate a panel of genes involved in adaptive responses, including autophagy | |||
| TSC1 | GTPases | Germline mutations cause TSC | The TSC complex inhibits MTORCI via RHEB | van Slegtenhorst et al (1997); Inoki et al (2002) |
| TSC2 | ||||
| UVRAG | Component of class III PI3K complex | Monoallelically deleted in gastric and colorectal cancers | Positive modulator of BECN1 | Liang et al (2006); Kim et al (2008); Zhao et al (2012) |
| VHL | E3 ubiquitin ligase | Germline mutations cause the von Hippel–Lindau syndrome | Inhibits LC3B and TRPM3 via miR-204 | Seizinger et al (1988); Shuin et al (1994); Tracy et al (2007); Zhang et al (2008); Bellot et al (2009); Wilkinson et al (2009); Mikhaylova et al (2012); Hall et al (2014) |
| Sporadically mutated in a large fraction of RCC | Inhibits the HIF-1-dependent synthesis of BNIP3 and BNIP3L | |||
AKT1, v-akt murine thymoma viral oncogene homolog 1; AMBRA1, autophagy/beclin-1 regulator 1; AMPK, 5′-AMP-activated protein kinase; BCL2, B-cell CLL/lymphoma 2; BECN1, Beclin 1; BNIP3, BCL2/adenovirus E1B 19 kDa interacting protein 3; BNIP3L, BNIP3-like; BRAF, B-Raf proto-oncogene, serine/threonine kinase, CDKN2A, cyclin-dependent kinase inhibitor 2A; DAPK1, death-associated protein kinase 1; DIRAS3, DIRAS family, GTP-binding RAS-like 3; DRAM1, DNA-damage-regulated autophagy modulator 1; EGFR, epidermal growth factor receptor; ER, endoplasmic reticulum; FOXO1, forkhead box O1; FUNDC1, FUN14 domain containing 1; HIF-1, hypoxia-inducible factor 1; HPV, human papillomavirus; HRAS, Harvey rat sarcoma viral oncogene homolog; KRAS, Kirsten rat sarcoma viral oncogene homolog; MTORCI, mechanistic target of rapamycin complex I; MYC, v-myc avian myelocytomatosis viral oncogene homolog; MYCL, v-myc avian myelocytomatosis viral oncogene lung carcinoma-derived homolog; MYCN, v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog; NF1, neurofibromin 1; NRAS, neuroblastoma RAS viral (v-ras) oncogene homolog; PDPK1, phosphoinositide-dependent protein kinase 1; PHTS, PTEN hamartoma tumor syndrome; PI3K, phosphoinositide-3-kinase; PTEN, phosphatase and tensin homolog; RB1, retinoblastoma 1; RCC, renal cell carcinoma; RHEB, Ras homolog enriched in brain; RTK, receptor tyrosine kinase; SCC, squamous cell carcinoma; TP53, tumor protein p53; TRPM3, transient receptor potential nonselective cation channel, subfamily M, member 3; TSC, tuberous sclerosis; ULK1, unc-51-like autophagy-activating kinase 1; UVRAG, UV radiation resistance associated; VHL, von Hippel–Lindau tumor suppressor; XIAP, X-linked inhibitor of apoptosis.