A novel interaction between hScrib and PP1γ downregulates ERK signaling and suppresses oncogene-induced cell transformation.
Previous studies have shown that the cell polarity regulator hScrib interacts with, and consequently controls, the ERK signaling pathway. This interaction occurs through two well-conserved Kinase Interacting Motifs, which allow hScrib to bind ERK1 directly, resulting in a reduction in the levels of phospho-ERK. This suggests that hScrib might recruit a phosphatase to regulate this signaling pathway. Using a proteomic approach we now show that Protein Phosphatase 1γ (PP1γ) is a major interacting partner of hScrib. This interaction is direct and occurs through a conserved PP1γ interaction motif on the hScrib protein, and this interaction appears to be required for hScrib's ability to downregulate ERK phosphorylation. In addition, hScrib also controls the pattern of PP1γ localization, where loss of hScrib enhances the nuclear translocation of PP1γ. Furthermore, we also show that the ability of hScrib to interact with PP1γ is important for the ability of hScrib to suppress oncogene-induced transformation of primary rodent cells. Taken together, these results demonstrate that hScrib acts as a scaffold to integrate the control of the PP1γ and ERK signaling pathways and explains how disruption of hScrib localisation can contribute towards the development of human malignancy.
Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
Kazunori
K
Nagasaka
Takayuki
T
Seiki
Aki
A
Yamashita
Paola
P
Massimi
Vanitha Krishna
VK
Subbaiah
Miranda
M
Thomas
Christian
C
Kranjec
Kei
K
Kawana
Shunsuke
S
Nakagawa
Tetsu
T
Yano
Yuji
Y
Taketani
Tomoyuki
T
Fujii
Shiro
S
Kozuma
Lawrence
L
Banks
D000595:Amino Acid Sequence; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009857:Oncogenes; D010766:Phosphorylation; D011485:Protein Binding; D054645:Protein Phosphatase 1 / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism*
D008565:Membrane Proteins; C480591:SCRIB protein, human; D025521:Tumor Suppressor Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D054645:Protein Phosphatase 1