MEK Binding to Ksr Promotes Allosteric Activation of Braf the RAF Family Kinases (ARAF, BRAF, and CRAF) Have Domains

Published OnlineFirst February 23, 2018; DOI: 10.1158/2159-8290.CD-RW2018-033

REsEARCh wATCh

Immunology

Major finding: Natural killer (NK) cells re- Concept: NK cells produce the chemo- Impact: Chemokines may represent cruit conventional type 1 dendritic cells kines CCL5 and XCL1 to recruit cDC1, therapeutic targets to enhance cDC1

(cDC1) to the tumor microenvironment . which is blocked by tumor-derived PGE2 . recruitment and antitumor immunity . nAturAL KiLLEr cELLs rEcruit dEndritic cELLs to ProMotE AntituMor iMMunitY Conventional type 1 dendritic cells (cDC1) production of CCL5 and XCL1, and reduced NK-cell mote antitumor immunity and are linked to survival, thereby preventing cDC1 recruitment. response to immunotherapy. However, cDC1 are Similarly, blocking CCL5 and XCL1 reduced rarely found in the tumor microenvironment cDC1 accumulation in vivo, whereas expressing (TME) of human tumors, and the mechanisms CCL5 and XCL1, in tumors that do not express that control their abundance are not understood. PGE2, increased cDC1 accumulation in the TME Strategies to increase cDC1 abundance might and suppressed tumor growth. However, expres- potentially enhance the antitumor immunity and sion of CCL5 and XCL1 was not suffi cient to suppress tumor progression. Prostaglandin E2 recruit cDC1 in PGE2-producing tumors, in part (PGE2) suppresses antitumor immunity and is secreted by due to a PGE2-mediated downregulation of XCR1. Analysis many tumors, and Böttcher and colleagues found that cDC1 of data from The Cancer Genome Atlas revealed that the NK accumulate in the tumor microenvironment in BRAFV600E cell and cDC1 gene signatures were associated with expres- melanomas when the cyclooxygenases (COX) required for sion of XCL1, XCL2 (a human paralog of XCL1), and CCL5, PGE2 production (Pgts1 and Pgts2) are deleted from tumor and these signatures were linked to extended patient sur- cells. This fi nding suggested that tumor-derived PGE2 may vival. Altogether, these fi ndings reveal a mechanism by which disrupt cDC1 accumulation. The accumulation of cDC1 in NK cells facilitate cDC1 recruitment to promote antitumor the tumor microenvironment required natural killer (NK) immunity, and suggest the potential for therapeutic targeting V600E cells in COX-defi cient BRAF melanoma cells, and NK- of cDC1-attracting chemokines and PGE2. n cell depletion accelerated tumor growth. Mechanistically, NK cells produced the chemokines XCL1 and CCL5, thereby Böttcher JP, Bonavita E, Chakravarty P, Blees H, Cabeza-Cabre- facilitating the recruitment of cDC1 to tumors, as cDC1 rizo M, Sammicheli S, et al. NK cells stimulate recruitment of cDC1 express both the XCL1 receptor XCR1 and the CCL5 recep- into the tumor microenvironment promoting cancer immune control. tors CCR1 and CCR5. Conversely, PGE2 reduced NK-cell pro- Cell 2018;172:1022–37.e14.

structural Biology

Major finding: KSR–MEK complexes al- Concept: BRAF and KSR interact via Impact: Disrupting BRAF N-terminal reg- losterically activate BRAF, which then the BRAF N-terminal BRS and KSR ulatory regions may suppress allosteric phosphorylates a second MEK molecule . coiled-coil sterile α motif domains . activation and oncogenic signaling .

MEK binding to Ksr ProMotEs ALLostEric ActivAtion of brAf The RAF family kinases (ARAF, BRAF, and CRAF) have domains. Specifi cally, the BRAF–KSR interaction occurred emerged as potential therapeutic targets in cancer as they are through the N-terminal coiled-coil-sterile α motif of KSR1 and activated by oncogenic RAS signaling and in turn phospho- the N-terminal BRAF-specifi c (BRS) domain of BRAF. Deter- rylate MEK to activate downstream MAPK signaling. The mination of the BRS domain crystal structure to 2.1 Å revealed pseudokinases KSR1 and KSR2 have been reported to act as that it is comprised of two antiparallel α-helices connected scaffolds, promoting the interaction between RAF and MEK. by an α-hairpin. Mechanistically, MEK1 binding to KSR1 via However, the structural mechanism by which KSR1/2 interact the helix αG facilitated KSR1 side-to-side dimerization with with and regulate the activity of RAF proteins has not been BRAF, thereby allosterically activating BRAF and allowing it fully elucidated. Lavoie, Sahmi, Maisonneuve, and colleagues to phosphorylate a second MEK substrate molecule bound identifi ed a mechanism by which KSR promotes allosteric to the BRAF helix αG. Collectively, these fi ndings reveal a role activation of BRAF. Binding of MEK to the kinase domain for KSR in promoting MEK-dependent allosteric activation of of KSR induced heterodimerization of the BRAF and KSR1 BRAF, and suggest the potential for targeting MAPK signaling kinase domains independent of MEK catalytic activity, and this by disrupting the BRAF N-terminal regulatory region. n event was suffi cient to promote BRAF activation. The KSR– MEK interaction was also required for KSR-mediated BRAF Lavoie H, Sahmi M, Maisonneuve P, Marullo SA, Thevakumaran activation. Further, the BRAF-KSR association required the N, Jin T, et al. MEK drives BRAF activation through allosteric control side-to-side dimerization surface of the BRAF and KSR kinase of KSR proteins. Nature 2018;554:549–53.

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APRIL 2018 CANCER DISCOVERY | 385

MEK Binding to KSR Promotes Allosteric Activation of BRAF

Cancer Discov 2018;8:385. Published OnlineFirst February 23, 2018.

Updated version Access the most recent version of this article at: doi:10.1158/2159-8290.CD-RW2018-033

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