Table 1.
Genes targeted in the siRNA library
| Gene category and name | GenBank accession no. | Protein namea | Biochemical activityb | Biological function(s) | Reference(s) |
|---|---|---|---|---|---|
| Category I. Genes encoding proteins that bind subunits of type IA PI 3-kinase | |||||
| Rab GTPase genes | |||||
| RAB4A | NM_004578 | Rab4a | Rab GTPase; binds p85 regulatory subunit of PI 3-kinase | Receptor recycling, exocytosis | 15 |
| RAB4B | NM_016154 | Rab4b | Rab GTPase; binds p85 regulatory subunit of PI 3-kinase | Receptor recycling, exocytosis | 15 |
| RAB5A | NM_004162 | Rab5a | Rab GTPase; binds p85 and p110 subunits of PI 3-kinase | Endocytosis (formation and fusion of clathrin-coated vesicles) | 15 |
| RAB5B | NM_002868 | Rab5b | Rab GTPse; binds p85 and p110 subunits of PI 3-kinase | Endocytosis (formation and fusion of clathrin-coated vesicles) | 15 |
| RAB5C | NM_201434 | Rab5c | Rab GTPsae; binds p85 and p110 subunits of PI 3-kinase | Endocytosis (formation and fusion of clathrin-coated vesicles) | 15 |
| Ras GTPase genes | |||||
| HRAS | NM_004985 | H-Ras | Ras GTPase; binds and activates p110 catalytic subunit of PI 3-kinase | Actin cytoskeleton, cell growth | 12 |
| KRAS2 | NM_004985 | Ki-Ras2 | Ras GTPase; binds and activates p110 catalytic subunit of PI 3-kinase | Actin cytoskeleton, cell growth | 12 |
| MRAS | NM_012219 | M-Ras/R-Ras3 | Ras GTPase; binds and activates p110 catalytic subunit of PI 3-kinase | Actin cytoskeleton | 12 |
| NRAS | NM_002524 | N-Ras | Ras GTPase; binds and activates p110 catalytic subunit of PI 3-kinase | Actin cytoskeleton, cell growth | 12 |
| RRAS2 | NM_012250 | R-Ras2/TC21 | Ras GTPase; binds and activates p110 catalytic subunit of PI 3-kinase | Actin cytoskeleton | 12 |
| Miscellaneous | |||||
| APPL | NM_012096 | APPL | Adaptor protein; binds p110 | Enhancer of Akt1 activation | 61 |
| CBL | NM_005188 | Cbl | E3 ubiquitin ligase; binds p85 regulatory subunit of PI 3-kinase | Ubiquitination, receptor trafficking, actin cytoskeleton | 43, 83 |
| CTNNB1 | NM_001904 | Beta-catenin | Component of adherens junctions; binds p85 regulatory subunit of PI 3-kinase | Cell-cell junctions, transcriptional regulation | 90 |
| PIK3IP1 | NM_052880 | PI 3-kinase-interacting protein 1 | Transmembrane protein containing kringle motifs; binds and inhibits p110 catalytic subunit of PI 3-kinase | Apoptosis | 97 |
| PTK2 | NM_153831 | FAK/PTK2 | Cytosolic tyrosine kinase; binds p85 regulatory subunit of PI 3-kinase, stimulates PI 3-kinase activity | Cell adhesion and migration | 17 |
| Category II. Genes encoding proteins that bind PI(3,4,5)P3 and/or PI(3,4)P2 | |||||
| Ser/Thr kinases | |||||
| AKT1 | NM_005163 | Akt1/protein kinase B1 | Serine/threonine kinase; substrates include BAD, forkhead transcription factors, GSK-α, GSK-β, ERM proteins; PH domain binds PI(3,4)P2 and PI(3,4,5)P3 | Cell survival, growth, motility | 49, 58 |
| AKT2 | NM_001626 | Akt2/protein kinase B2 | Serine/threonine kinase; substrates likely the same as those of Akt1; PH domain binds PI(3,4)P2 and PI(3,4,5)P3 | Cell survival, growth, motility, insulin-induced glucose uptake, tumorigenesis | 49 |
| ILK | NM_004517 | Integrin-linked kinase | Serine/threonine kinase; substrates include MLC-20 and MYPT1; PH domain binds PI(3,4,5)P3 | Integrin-mediated cell adhesion and survival | 38 |
| PDPK1 | NM_002613 | PDK1 | Serine/threonine kinase; substrates include Akt, protein kinase C (PKC isoforms), PAK1, PAK2, p70S6 kinase, and SGK1; PH domain binds PI(3,4)P2 and PI(3,4,5)P3 | Cell survival, growth, motility, insulin signaling, T-cell differentiation | 3 |
| Regulators of Arf GTPases | |||||
| ARAP3 | NM_022481 | ARAP3/centaurin δ-3 | GAP for Arf6 and RhoA; binds PI(3,4,5)P3 through PH domains | Actin cytoskeleton, cell motility | 51 |
| CENTA1 | NM_006869 | Centaurin α-1 | GAP for Arf6; binds PI(3,4,5)P3, probably through PH domain(s) | Actin cytoskeleton, cell migration | 86 |
| CENTD1 | NM_139182 | ARAP2/centaurin δ-1 | GAP for Arf6; PI(3,4,5)P3 stimulates GAP activity, possibly by binding PH domain(s) | Actin cytoskeleton, focal adhesions | 93 |
| CENTD2 | NM_015242 | ARAP1/centaurin δ-2 | GAP for Arf1, Arf5, RhoA, and, Cdc42; PH domain binds PI(3,4,5)P3 | Golgi structure, actin cytoskeleton | 62 |
| GIT1 | NM_014030 | GIT1 | GAP for Arf1, Arf2, Arf3, Arf5, and Arf6; PI(3,4,5)P3 stimulates GAP activity | Actin cytoskeleton, focal adhesions, membrane trafficking | 41, 88 |
| GIT2 | NM_057169 | GIT2 | GAP for Arf1, Arf2, Arf3, Arf5, and Arf6; PI(3,4,5)P3 stimulates GAP activity | Actin cytoskeleton, focal adhesions, membrane trafficking | 41, 88 |
| PSCD1 | NM_004762 | Cytohesin-1/PSCD1 | GEF for Arf1 and Arf3; PH domain binds PI(3,4,5)P3 | Integrin-mediated cell adhesion | 26, 50 |
| PSCD2 | NM_017457 | ARNO/cytohesin-2, PSCD2 | GEF for Arf1 and Arf6; PH domain binds PI(3,4,5)P3 | Actin cytoskeleton, membrane trafficking, integrin recycling | 26, 87 |
| PSCD3 | NM_004227 | Grp1/cytohesin-3/PSCD3 | GEF for Arf1, Arf3, and Arf6; PH domain binds PI(3,4,5)P3 | Membrane trafficking, Golgi function, cell adhesion | 26, 55 |
| Regulators of Rac, and/or Cdc42 GTPases | |||||
| ARHGAP9 | NM_032496 | Rho-type GTPase-activating protein 9 | GAP for Cdc42 and Rac1; PH domain binds PI(3,4,5)P3 | Cell adhesion | 13 |
| ARHGEF6 | NM_004840 | α-PIX/Rac/Cdc42 GEF 6/Cool-2 | GEF for Rac and Cdc42 | Cell adhesion | 94 |
| DAPP1 | NM_014395 | DAPP1/Bam32 | Adaptor protein; enhances Rac activity; PH domain binds PI(3,4)P2 and PI(3,4,5)P3 | Actin cytoskeleton | 28 |
| DEPDC2 | NM_024870 | P-REX2/DEPDC2 | GEF for Rac | Actin cytoskeleton | 25 |
| DOCK1 | NM_001380 | Dock180 | GEF for Rac; DHR1 domain binds PI(3,4,5)P3 | Actin cytoskeleton, cell motility, phagocytosis | 20 |
| SOS1 | NM_005633 | Sos1 | GEF for Rac and Ras | Actin cytoskeleton, cell growth | 72 |
| SWAP70 | NM_015055 | SWAP70 | GEF for Rac | Actin cytoskeleton | 79 |
| TIAM1 | NM_003253 | Tiam1 | GEF for Rac; PH domain binds PI(3,4,5)P3 | Actin cytoskeleton, cell motility | 72 |
| VAV2 | NM_003371 | Vav2 | GEF for Rac; PH domain is thought to bind PI(3,4,5)P3 | Actin cytoskeleton | 36 |
| VAV3 | NM_006113 | Vav3 | GEF for Rac; PH domain is thought to bind PI(3,4,5)P3 | Actin cytoskeleton | 36 |
| Regulators of Ras GTPases | |||||
| RASA2 | NM_006506 | Gap1m | GAP for Ras; PH domain binds PI(3,4,5)P3 | Cell growth inhibitor | 92 |
| RASA3 | NM_007368 | Gap1/IP4BP | GAP for Ras and Rap; PH domain binds PI(3,4,5)P3 | Cell growth inhibitor | 92 |
| Lipid-modifying enzymes | |||||
| PLCG1 | NM_002660 | PLC-γ1 | Converts PI(4,5)P2 to IP3; PH domain binds PI(3,4,5)P3 | Actin cytoskeleton, cell growth, phagocytosis | 32 |
| PLD1 | NM_002662 | Phospholipase D1 | Converts phosphatidylcholine to phosphatidic acid, activated by PI(3,4,5)P3 or PI(3,4)P2; PH domain binds PI(3,4)P2 | Actin cytoskeleton, membrane trafficking | 71 |
| PLD2 | NM_002663 | Phospholipase D2 | Converts phosphatidylcholine to phosphatidic acid, activated by PI(3,4,5)P3 or PI(3,4)P2; PH domain binds PI(3,4)P2 | Actin cytoskeleton, membrane trafficking | 71 |
| Adaptor protein PLEKHA1 | NM_001001974 | PLEKHA1/TAPP1 | Adaptor protein; PH domain binds PI(3,4)P2 | Actin cytoskeleton, inhibition of insulin and PI 3-kinase pathways | 27 |
| Miscellaneous | |||||
| BMX | NM_203281 | Bmx/Etk | Tec family tyrosine kinase; PH domain binds PI(3,4,5)P3 | Cell growth, motility, apoptosis | 80 |
| MYOX | NM_012334 | Myosin X | Actin-dependent motor protein; PH domains bind PI(3,4,5)P3 | Contractility, phagocytosis | 21, 69 |
| SNX1 | NM_003099 | Sorting nexin-1 | PX domain binds PI(3,4,5)P3 | Endocytosis, receptor trafficking | 96 |
| SNX5 | NM_152227 | Sorting nexin-5 | PX domain binds PI(3,4)P2 | Endocytosis, receptor recycling from endosomes to the Golgi | 60 |
| Category III. Genes encoding proteins indirectly regulated by type IA PI 3-kinase | |||||
| FRAP1 | NM_004958 | mTor/FRAP1 | Ser/Thr kinase; regulated by Akt; substrates include Akt, PKC-α, PKC-δ, p70S6 kinase, SGK1 | Regulation of protein synthesis, cell migration | 33, 75, 91 |
| GSK3A | NM_019884 | Glycogen synthase kinase-3α | Regulates glycogen synthase; substrate of Akt proteins | Cell survival, tumorigenesis, regulation of gene expression | 75 |
| GSK3B | NM_002093 | Glycogen synthase kinase-3β | Regulates glycogen synthase; substrate of Akt proteins | Cell survival, tumorigenesis, regulation of gene expression | 75 |
| PAK1 | NM_002576 | PAK1 | Ser/Thr kinase; phosphorylated by PDK1 | Actin cytoskeleton, cell migration | 30 |
| PAK2 | NM_002577 | PAK2 | Ser/Thr kinase; phosphorylated by PDK1 | Actin cytoskeleton, cell migration | 30 |
| PKN1 | NM_213560 | Protein kinase N1 | Ser/Thr kinase; phosphorylated by PDK1; substrates include α-actinin, adducin, and cortactin | Actin cytoskeleton, cell migration, membrane trafficking, exocytosis | 64 |
| PKN2 | NM_006256 | Protein kinase N2 | Ser/Thr kinase; phosphorylated by PDK1; substrates include α-actinin, adducin, and cortactin | Actin cytoskeleton, cell migration, cell adhesion | 64 |
| PRKCD | NM_006254 | PKC-δ | Ser/Thr kinase; phosphorylated by PDK1 and mTor; substrates include MARCKS, ERM proteins, adducin | Actin cytoskeleton; cell migration | 53, 74 |
| PRKCE | NM_005400 | PKC-ε | Ser/Thr kinase; phosphorylated by PDK1 and mTor; substrates include MARCKS, ERM proteins, adducin | Actin cytoskeleton; cell migration | 53, 74 |
| PRKCG | NM_002739 | PKC-γ | Ser/Thr kinase; phosphorylated by PDK1; substrates include MARCKS, ERM proteins, adducin | Actin cytoskeleton; cell migration | 53, 74 |
| PRKCI | NM_002740 | PKC-ι | Ser/Thr kinase; substrate of PDK1; substrates include MARCKS, ERM proteins, adducin | Actin cytoskeleton | 53, 74 |
| PRKCQ | NM_006257 | PKC-θ | Ser/Thr kinase; phosphorylated by PDK1; substrates include MARCKS, ERM proteins, adducin | Actin cytoskeleton; cell migration | 53, 74 |
| PRKCZ | NM_002744 | PKC-ζ | Ser/Thr kinase; phosphorylated by PDK1; substrates include MARCKS, ERM proteins, adducin | Actin cytoskeleton, cell polarity | 53, 74 |
| RPS6KA1 | NM_002953 | P70S6 kinase 1/RSK1 | Substrate of PDK1; phosphorylates several transcription factors, including SRF and c-Fos | Regulation of translation, cell growth | 75 |
| RPS6KA3 | NM_004586 | P70 S6 kinase 2/RSK2 | Substrate of PDK1; phosphorylates several transcription factors, including SRF and c-Fos | Regulation of translation, cell growth | 75 |
| SGK1 | NM_005627 | Serum/glucocorticoid-regulated kinase 1 | Ser/Thr kinase; phosphorylated by PDK1 and mTor; substrates include NEDD4L and FOXO3A | Cell survival, ion transport | 10 |
a
FAK, focal adhesion kinase; PTK2, protein tyrosine kinase 2; PDK1, 3-phosphoinositide-dependent kinase 1; PLC-γ1, phospholipase C-γ1; PKC, protein kinase C.
b
GAP, GTPase-activating protein; GEF, guanine nucleotide exchange factor.