Targeted genetic dependency screen facilitates identification of actionable mutations in FGFR4, MAP3K9, and PAK5 in lung cancer

Fawdar, Shameem; Trotter, Eleanor W.; Li, Yaoyong; Stephenson, Natalie L.; Hanke, Franziska; Marusiak, Anna A.; Edwards, Zoe C.; Ientile, Sara; Waszkowycz, Bohdan; Miller, Crispin; Brognard, John

doi:10.1073/pnas.1305207110

Cited by 51 publications

(49 citation statements)

References 37 publications

(45 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In lung and colon cancers, PAK5 is observed to be particularly susceptible to acquisition of in-frame missense mutations (87,88), although PAK4 somatic mutation has also been found to be associated with cancer (84,89). Although these mutations do not cluster to specific regions within the proteins, one tumor-associated PAK5 mutant was demonstrated to have increased signaling, presumably due to increased kinase activity.…”

Section: Alteration Of Type II Pak Signaling In Cancermentioning

confidence: 99%

“…Although these mutations do not cluster to specific regions within the proteins, one tumor-associated PAK5 mutant was demonstrated to have increased signaling, presumably due to increased kinase activity. Interestingly, the mutation (T538N) maps to the catalytic cleft, suggesting release of pseudosub-strate inhibition as a potential mechanism (87). A recurrent PAK6 mutation at the central Pro residue in the pseudosubstrate region (P52L) found in melanomas (90,91) resulted in increased catalytic activity (56).…”

Section: Alteration Of Type II Pak Signaling In Cancermentioning

confidence: 99%

See 1 more Smart Citation

Signaling, Regulation, and Specificity of the Type II p21-activated Kinases

Ha¹,

Morse

Turk³

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

The p21-activated kinases (PAKs) are a family of six serine/ threonine kinases that act as key effectors of RHO family GTPases in mammalian cells. PAKs are subdivided into two groups: type I PAKs (PAK1, PAK2, and PAK3) and type II PAKs (PAK4, PAK5, and PAK6). Although these groups are involved in common signaling pathways, recent work indicates that the two groups have distinct modes of regulation and have both unique and common substrates. Here, we review recent insights into the molecular level details that govern regulation of type II PAK signaling. We also consider mechanisms by which signal transduction is regulated at the level of substrate specificity. Finally, we discuss the implications of these studies for clinical targeting of these kinases.The type II PAKs 2 are members of the Sterile 20 (Ste20) family of STE (homologs of yeast Sterile 7, Sterile 11, and Sterile 20) group serine/threonine kinases. They are important for signaling from small GTPases of the RHO family, particularly the CDC42 (cell division cycle 42) and to a lesser extent RAC (Rasrelated C3 botulinum toxin substrate) isoforms, to the actin cytoskeleton and to growth and survival pathways. Type II PAKs share significant sequence similarity with the well studied type I PAKs (PAK1, PAK2, and PAK3), which are extensively reviewed elsewhere (1-5), but the roles of the type I and type II PAKs in GTPase signaling pathways, and their mechanisms of regulation, differ considerably. In the sections below, we consider the function of the type II PAK serine/threonine kinases in small GTPase pathways, the structural and biochemical basis for their regulation, mechanisms of their targeting to substrates, and some of the current strategies for targeted small molecule inhibition of these enzymes. Type II PAKs in Signal TransductionThe type II PAKs are binding partners of RHO family small GTPases. Their dominant role in signal transduction is as serine/threonine kinases, where transfer of the ␥-phosphate from an ATP molecule to a substrate protein results in consequent regulation of downstream effector pathways. The activation of type II PAK kinase signaling is associated with small GTPase binding, but as discussed below, direct activation does not seem to occur upon small GTPase binding. Rather, GTPases are thought to primarily regulate type II PAKs by controlling their subcellular localization. Type II PAKs also have reported kinase-independent roles as scaffolding proteins, with functions that are still emerging.The type II PAKs are placed at critical nodal points in multiple signaling pathways that are associated with cell growth, cytoskeletal dynamics, cell polarity, survival, and development (6 -8). They are located directly downstream of RHO family GTPase activation. Numerous substrates of type II PAKs have been identified that are thought to act as downstream effectors in distinct cellular processes. For example, direct phosphorylation of LIM kinases (9, 10), p210/␤-catenin (11, 12), slingshot phosphatase (SSH) (13), 14), and PDZ-RHOGEF (15) has...

show abstract

Section: Alteration Of Type II Pak Signaling In Cancermentioning

confidence: 99%

Section: Alteration Of Type II Pak Signaling In Cancermentioning

confidence: 99%

Signaling, Regulation, and Specificity of the Type II p21-activated Kinases

Ha¹,

Morse

Turk³

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…MAP3K4 has been proposed to mediate the TGFβ-induced phosphorylation of p38 MAPK through SMAD-dependent expression of GADD45β, which associates with and activates MAP3K4 and play as an oncogene [19]. MAP3K9 is a member of the mixed lineage family of kinases and is composed of an SH3 domain, Ser/Thr kinase domain, and a Cdc42/Rac interactive binding (CRIB) domain [20]. We observed that inhibition of MAP3K4 or MAP3K significantly decreased cell proliferation in CSCC.…”

Section: Discussionmentioning

confidence: 85%

Role of miR-148a in cutaneous squamous cell carcinoma by repression of MAPK pathway

Luo

Tian

et al. 2015

Archives of Biochemistry and Biophysics

View full text Add to dashboard Cite

“…We used various inhibitors against ERK, JNK and p38 MAPKs, and TGF-β1 induced FGFR4 expression via the ERK pathway in HCC. Previous studies reported that changes in FGFR4 expression may activate ERK pathways in lung cancer [29], prostate cancer [30], and studies show that low expression of FGFR4 may cause reduced ERK pathway signaling in breast cancer [31]. Thus, crosstalk among TGF-β1, FGFR4 and the ERK pathway requires more study.…”

Section: Discussionmentioning

confidence: 99%

TGF-β1 Promotes Hepatocellular Carcinoma Invasion and Metastasis via ERK Pathway-Mediated FGFR4 Expression

Huang¹,

Qiu²,

Wan³

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: TGF-β1 is beneficial during early liver disease but is tumor-progressive during late stages especially for hepatocellular carcinoma (HCC). Thus, exploring the underlying mechanisms may provide information about a potentially therapeutic role of TGF-β1 in HCC. Methods: Western blot and real-time quantitative PCR were used to quantify FGFR4 expression in HCC cell lines and a normal liver cell line. After constructing the best silencing FGFR4 expression vector, migration and invasiveness of TGF-β1 in HCC was studied in vitro and in vivo. Western blot was used to study the mechanism of TGF-β1 induction on FGFR4 expression with various inhibitors. Results: HepG2 cell lines had the most FGFR4 expression, and data show that silencing FGFR4 suppressed cell proliferation, invasion and migration in HCC induced by TGF-β1 in vitro and in vivo. Moreover, TGF-β1 induced FGFR4 expression through the ERK pathway. Conclusion: Promoting FGFR4 expression via the ERK pathway, TGF-β1 contributes to HCC invasion and metastasis.

show abstract

Targeted genetic dependency screen facilitates identification of actionable mutations in FGFR4, MAP3K9, and PAK5 in lung cancer

Cited by 51 publications

References 37 publications

Signaling, Regulation, and Specificity of the Type II p21-activated Kinases

Signaling, Regulation, and Specificity of the Type II p21-activated Kinases

Role of miR-148a in cutaneous squamous cell carcinoma by repression of MAPK pathway

TGF-β1 Promotes Hepatocellular Carcinoma Invasion and Metastasis via ERK Pathway-Mediated FGFR4 Expression

Contact Info

Product

Resources

About