TY - JOUR
T1 - PLEKHA7 signaling is necessary for the growth of mutant KRAS driven colorectal cancer
AU - Jeung, Hei Cheul
AU - Puentes, Roisin
AU - Aleshin, Alexander
AU - Indarte, Martin
AU - Correa, Ricardo G.
AU - Bankston, Laurie A.
AU - Layng, Fabiana I.A.L.
AU - Ahmed, Zamal
AU - Wistuba, Ignacio
AU - Yao, Yong
AU - Duenas, Daniela G.
AU - Zhang, Shuxing
AU - Meuillet, Emmanuelle J.
AU - Marassi, Francesca
AU - Liddington, Robert C.
AU - Kirkpatrick, Lynn
AU - Powis, Garth
N1 - Publisher Copyright:
© 2021
PY - 2021/12/15
Y1 - 2021/12/15
N2 - Plekha7 (Pleckstrin homology [PH] domain containing, family A member 7) regulates the assembly of proteins of the cytoplasmic apical zonula adherens junction (AJ), thus ensuring cell-cell adhesion and tight-junction barrier integrity. Little is known of Plekha7 function in cancer. In colorectal cancer (CRC) Plekha7 expression is elevated compared to adjacent normal tissue levels, increasing with clinical stage. Plekha7 was present at plasma membrane AJ with wild-type KRas (wt-KRas) but was dispersed in cells expressing mutant KRas (mut-KRas). Fluorescence lifetime imaging microscopy (FLIM) indicated a direct Plekha7 interaction with wt-KRas but scantily with mut-KRas. Inhibiting Plekha7 specifically decreased mut-KRas cell signaling, proliferation, attachment, migration, and retarded mut-KRAS CRC tumor growth. Binding of diC8-phosphoinositides (PI) to the PH domain of Plekha7 was relatively low affinity. This may be because a D175 amino acid residue plays a “sentry” role preventing PI(3,4)P2 and PI(3,4,5)P3 binding. Molecular or pharmacological inhibition of the Plekha7 PH domain prevented the growth of mut-KRas but not wt-KRas cells. Taken together the studies suggest that Plekha7, in addition to maintaining AJ structure plays a role in mut-KRas signaling and phenotype through interaction of its PH domain with membrane mut-KRas, but not wt-KRas, to increase the efficiency of mut-KRas downstream signaling.
AB - Plekha7 (Pleckstrin homology [PH] domain containing, family A member 7) regulates the assembly of proteins of the cytoplasmic apical zonula adherens junction (AJ), thus ensuring cell-cell adhesion and tight-junction barrier integrity. Little is known of Plekha7 function in cancer. In colorectal cancer (CRC) Plekha7 expression is elevated compared to adjacent normal tissue levels, increasing with clinical stage. Plekha7 was present at plasma membrane AJ with wild-type KRas (wt-KRas) but was dispersed in cells expressing mutant KRas (mut-KRas). Fluorescence lifetime imaging microscopy (FLIM) indicated a direct Plekha7 interaction with wt-KRas but scantily with mut-KRas. Inhibiting Plekha7 specifically decreased mut-KRas cell signaling, proliferation, attachment, migration, and retarded mut-KRAS CRC tumor growth. Binding of diC8-phosphoinositides (PI) to the PH domain of Plekha7 was relatively low affinity. This may be because a D175 amino acid residue plays a “sentry” role preventing PI(3,4)P2 and PI(3,4,5)P3 binding. Molecular or pharmacological inhibition of the Plekha7 PH domain prevented the growth of mut-KRas but not wt-KRas cells. Taken together the studies suggest that Plekha7, in addition to maintaining AJ structure plays a role in mut-KRas signaling and phenotype through interaction of its PH domain with membrane mut-KRas, but not wt-KRas, to increase the efficiency of mut-KRas downstream signaling.
KW - Mutant KRAS
KW - PH domain
KW - PLEKHA7
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U2 - 10.1016/j.yexcr.2021.112930
DO - 10.1016/j.yexcr.2021.112930
M3 - Article
C2 - 34800542
AN - SCOPUS:85119376654
SN - 0014-4827
VL - 409
JO - Experimental Cell Research
JF - Experimental Cell Research
IS - 2
M1 - 112930
ER -