PP2A Inactivation Mediated by PPP2R4 Haploinsufficiency Promotes Cancer Development

Homozygously targeted Ppp2r4 knockout mice (hypomorphic allele) with severely affected PTPA expression (on average only 20% of wild-type levels in most tissues) were born at less than Mendelian ratios, suggestive of embryonic lethality.

“For instance, homozygously targeted Ppp2r4 KO mice (hypomorphic allele), with severely affected expression of the PP2A activator PTPA (Phosphatase Two A Phosphatase Activator) (on average only 20% of WT levels were left in most tissues), were born at less than Mendelian ratios, suggestive for embryonic lethality [43].”

A selective decrease in PP2A-B56γ/ε activity was found in PTPA knockout, while PP2A-B55 activity was unaffected.

“Interestingly, however, a selective decrease in PP2A-B56γ/ε activity was found, while PP2A-B55 activity was unaffected.”

In surviving PTPA knockout mice, overall PP2A-C methylation and activity were significantly reduced (50%).

“In the surviving PTPA KO mice, overall PP2A-C methylation and activity were significantly reduced (50%).”

In Ppp2r4 gt/+ mice, overall survival is decreased.

“-Embryonic lethality suggested; decreased overall survival in gt/+ mice [43]”

Accelerated DMBA/TPA-induced skin papillomas are also observed in heterozygous PTPA knockout mice, in which PP2A-B56γ/ε activity is selectively decreased.

“Notably, accelerated occurrence of DMBA/TPA-induced skin papillomas was also observed in heterozygous PTPA KO mice, in which activity of PP2A-B56γ/ε (and presumably other PP2A-B56 isoforms) was selectively decreased [43].”

In mice with a gene-trap insertion in the first intron of Ppp2r4 (hypomorphic PTPA allele), embryonic lethality is suggested.

“-Embryonic lethality suggested; decreased overall survival in gt/+ mice [43]”

The spontaneous tumor phenotype in PTPA-deficient mice upon aging is less penetrant and mainly characterized by hematologic malignancies, less commonly HCC.

“The spontaneous tumor phenotype observed in PTPA-deficient mice upon aging, was somewhat less penetrant, and mainly characterized by the development of hematologic malignancies, and less commonly, of HCC.”

A prominent spontaneous cancer phenotype is observed in total-body constitutive B56δ knockout mice and in homozygous and heterozygous hypomorphic Ptpa mice.

“A very prominent spontaneous cancer phenotype was indeed observed in the total-body, constitutive KO model of the B56δ subunit [110] and in both homozygous and heterozygous mice of a hypomorphic Ptpa allele [43].”

In PTPA-deficient mouse tumors, no common signaling defects are revealed, although sporadic activation of Wnt, Hedgehog, and c-Myc signaling is present in some tumor tissues.

“In this case, no common signaling defects could be revealed, although sporadic activation of Wnt signaling (increased β-catenin expression), Hedgehog signaling (increased Gli1 expression) and c-Myc activation (Ser62 phosphorylation) were present in some of the tumor tissues analyzed [43].”

In Ppp2r4 gt/+ mice, DMBA/TPA-induced skin carcinogenesis is accelerated.

“-Accelerated DMBA/TPA-induced skin carcinogenesis in gt/+ mice”

In Ppp2r4 gt/+ and gt/gt mice older than 12 months, spontaneous cancer develops, mainly hematologic malignancies and less often HCC.

“-Spontaneous cancer development in gt/+ and gt/gt mice > 12 months: | mainly hematologic malignancies, less: HCC.”

In Ppp2r4 gt/gt tumors, Wnt, c-Myc and Hedgehog signaling are sporadically activated.

“-Sporadic activation of Wnt, c-Myc and Hedgehog signaling | in gt/gt tumors”

The Ppp2r4 gt allele lowers the activity of certain PP2A trimers, specifically B56-type but not B55.

“-Decreased activity of a selective set of PP2A trimers (B56-type, not | B55)”