Signaling Dynamics of the KSR1 Scaffold Complex

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2009 Jun 23

PMID 19541618

Citations 94

Authors

Melissa M McKay

Daniel A Ritt

Deborah K Morrison

Affiliations

Soon will be listed here.

Abstract

Scaffold proteins contribute to the spatiotemporal control of MAPK signaling and KSR1 is an ERK cascade scaffold that localizes to the plasma membrane in response to growth factor treatment. To better understand the molecular mechanisms of KSR1 function, we examined the interaction of KSR1 with each of the ERK cascade components, Raf, MEK, and ERK. Here, we identify a hydrophobic motif within the proline-rich sequence (PRS) of MEK1 and MEK2 that is required for constitutive binding to KSR1 and find that MEK binding and residues in the KSR1 CA1 region enable KSR1 to form a ternary complex with B-Raf and MEK following growth factor treatment that enhances MEK activation. We also find that docking of active ERK to the KSR1 scaffold allows ERK to phosphorylate KSR1 and B-Raf on feedback S/TP sites. Strikingly, feedback phosphorylation of KSR1 and B-Raf promote their dissociation and result in the release of KSR1 from the plasma membrane. Together, these findings provide unique insight into the signaling dynamics of the KSR1 scaffold and reveal that through regulated interactions with Raf and ERK, KSR1 acts to both potentiate and attenuate ERK cascade activation, thus regulating the intensity and duration of ERK cascade signaling emanating from the plasma membrane during growth factor signaling.

Citing Articles

Imaging the Raf-MEK-ERK Signaling Cascade in Living Cells.

Shin Y, Cho M, Hwang J, Myung K, Kweon H, Lee Z Int J Mol Sci. 2024; 25(19).

PMID: 39408915 PMC: 11477372. DOI: 10.3390/ijms251910587.

The mTOR pathway controls phosphorylation of BRAF at T401.

Christen D, Lauinger M, Brunner M, Dengjel J, Brummer T Cell Commun Signal. 2024; 22(1):428.

PMID: 39223665 PMC: 11370054. DOI: 10.1186/s12964-024-01808-2.

IQGAP3 Is an Important Mediator of Skin Inflammatory Diseases.

Zolotarenko A, Bruskin S Int J Mol Sci. 2024; 25(8).

PMID: 38674130 PMC: 11050236. DOI: 10.3390/ijms25084545.

Disruption of Ca/calmodulin:KSR1 interaction lowers ERK activation.

Thines L, Jang H, Li Z, Sayedyahossein S, Maloney R, Nussinov R Protein Sci. 2024; 33(5):e4982.

PMID: 38591710 PMC: 11002989. DOI: 10.1002/pro.4982.

SOS1 and KSR1 modulate MEK inhibitor responsiveness to target resistant cell populations based on PI3K and KRAS mutation status.

Daley B, Vieira H, Rao C, Hughes J, Beckley Z, Huisman D Proc Natl Acad Sci U S A. 2023; 120(47):e2313137120.

PMID: 37972068 PMC: 10666034. DOI: 10.1073/pnas.2313137120.

References

Schaeffer H, Catling A, Eblen S, Collier L, Krauss A, Weber M . MP1: a MEK binding partner that enhances enzymatic activation of the MAP kinase cascade. Science. 1998; 281(5383):1668-71. DOI: 10.1126/science.281.5383.1668. View

Muller J, Ory S, Copeland T, Piwnica-Worms H, Morrison D . C-TAK1 regulates Ras signaling by phosphorylating the MAPK scaffold, KSR1. Mol Cell. 2001; 8(5):983-93. DOI: 10.1016/s1097-2765(01)00383-5. View

McKay M, Morrison D . Integrating signals from RTKs to ERK/MAPK. Oncogene. 2007; 26(22):3113-21. DOI: 10.1038/sj.onc.1210394. View

Kornfeld K, Hom D, Horvitz H . The ksr-1 gene encodes a novel protein kinase involved in Ras-mediated signaling in C. elegans. Cell. 1995; 83(6):903-13. DOI: 10.1016/0092-8674(95)90206-6. View

Kolch W . Coordinating ERK/MAPK signalling through scaffolds and inhibitors. Nat Rev Mol Cell Biol. 2005; 6(11):827-37. DOI: 10.1038/nrm1743. View

Jacobs D, Glossip D, Xing H, Muslin A, Kornfeld K . Multiple docking sites on substrate proteins form a modular system that mediates recognition by ERK MAP kinase. Genes Dev. 1999; 13(2):163-75. PMC: 316390. View

Teis D, Wunderlich W, Huber L . Localization of the MP1-MAPK scaffold complex to endosomes is mediated by p14 and required for signal transduction. Dev Cell. 2002; 3(6):803-14. DOI: 10.1016/s1534-5807(02)00364-7. View

Pullikuth A, McKinnon E, Schaeffer H, Catling A . The MEK1 scaffolding protein MP1 regulates cell spreading by integrating PAK1 and Rho signals. Mol Cell Biol. 2005; 25(12):5119-33. PMC: 1140582. DOI: 10.1128/MCB.25.12.5119-5133.2005. View

Cacace A, Michaud N, Therrien M, Mathes K, Copeland T, Rubin G . Identification of constitutive and ras-inducible phosphorylation sites of KSR: implications for 14-3-3 binding, mitogen-activated protein kinase binding, and KSR overexpression. Mol Cell Biol. 1998; 19(1):229-40. PMC: 83881. DOI: 10.1128/MCB.19.1.229. View

10.

Morrison D, Davis R . Regulation of MAP kinase signaling modules by scaffold proteins in mammals. Annu Rev Cell Dev Biol. 2003; 19:91-118. DOI: 10.1146/annurev.cellbio.19.111401.091942. View

11.

Roy F, Laberge G, Douziech M, Ferland-McCollough D, Therrien M . KSR is a scaffold required for activation of the ERK/MAPK module. Genes Dev. 2002; 16(4):427-38. PMC: 155344. DOI: 10.1101/gad.962902. View

12.

Muller J, Cacace A, LYONS W, McGill C, Morrison D . Identification of B-KSR1, a novel brain-specific isoform of KSR1 that functions in neuronal signaling. Mol Cell Biol. 2000; 20(15):5529-39. PMC: 86003. DOI: 10.1128/MCB.20.15.5529-5539.2000. View

13.

Bashor C, Helman N, Yan S, Lim W . Using engineered scaffold interactions to reshape MAP kinase pathway signaling dynamics. Science. 2008; 319(5869):1539-43. DOI: 10.1126/science.1151153. View

14.

Shaul Y, Seger R . The MEK/ERK cascade: from signaling specificity to diverse functions. Biochim Biophys Acta. 2006; 1773(8):1213-26. DOI: 10.1016/j.bbamcr.2006.10.005. View

15.

Douville E, Warne P, Papin C, Laugier D, Calothy G, Downward J . Murine Ksr interacts with MEK and inhibits Ras-induced transformation. Curr Biol. 1998; 8(1):46-55. DOI: 10.1016/s0960-9822(98)70019-3. View

16.

Lee T, Hoofnagle A, Kabuyama Y, Stroud J, Min X, Goldsmith E . Docking motif interactions in MAP kinases revealed by hydrogen exchange mass spectrometry. Mol Cell. 2004; 14(1):43-55. DOI: 10.1016/s1097-2765(04)00161-3. View

17.

Casar B, Arozarena I, Sanz-Moreno V, Pinto A, Agudo-Ibanez L, Marais R . Ras subcellular localization defines extracellular signal-regulated kinase 1 and 2 substrate specificity through distinct utilization of scaffold proteins. Mol Cell Biol. 2008; 29(5):1338-53. PMC: 2643815. DOI: 10.1128/MCB.01359-08. View

18.

Ory S, Zhou M, Conrads T, Veenstra T, Morrison D . Protein phosphatase 2A positively regulates Ras signaling by dephosphorylating KSR1 and Raf-1 on critical 14-3-3 binding sites. Curr Biol. 2003; 13(16):1356-64. DOI: 10.1016/s0960-9822(03)00535-9. View

19.

Therrien M, Chang H, Solomon N, Karim F, Wassarman D, Rubin G . KSR, a novel protein kinase required for RAS signal transduction. Cell. 1995; 83(6):879-88. DOI: 10.1016/0092-8674(95)90204-x. View

20.

Catling A, Schaeffer H, Reuter C, Reddy G, Weber M . A proline-rich sequence unique to MEK1 and MEK2 is required for raf binding and regulates MEK function. Mol Cell Biol. 1995; 15(10):5214-25. PMC: 230769. DOI: 10.1128/MCB.15.10.5214. View