Capicua Regulates Cell Proliferation Downstream of the Receptor Tyrosine Kinase/Ras Signaling Pathway

Abstract

Signaling via the receptor tyrosine kinase (RTK)/Ras pathway promotes tissue growth during organismal development and is increased in many cancers [1]. It is still not understood precisely how this pathway promotes cell growth (mass accumulation). In addition, the RTK/Ras pathway also functions in cell survival, cell-fate specification, terminal differentiation, and progression through mitosis [2-7]. An important question is how the same canonical pathway can elicit strikingly different responses in different cell types. Here, we show that the HMG-box protein Capicua (Cic) restricts cell growth in Drosophila imaginal discs, and its levels are, in turn, downregulated by Ras signaling. Moreover, unlike normal cells, the growth of cic mutant cells is undiminished in the complete absence of a Ras signal. In addition to a general role in growth regulation, the importance of cic in regulating cell-fate determination downstream of Ras appears to vary from tissue to tissue. In the developing eye, the analysis of cic mutants shows that the functions of Ras in regulating growth and cell-fate determination are separable. Thus, the DNA-binding protein Cic is a key downstream component in the pathway by which Ras regulates growth in imaginal discs.

Loss of CIC and FUBP1 expressions are potential markers of shorter time to recurrence in oligodendroglial tumors

“…18 It was previously demonstrated that substitution mutation R505W (corresponding to R215W in human CIC) at the HMG box led to impaired eye development in Drosophila. 19 Moreover, the indels were predominantly of frameshift and small inframe deletions at functional domains including the HMG box and the CI motif that are predicted to disrupt CIC function. The mutation profile suggests that CIC function is likely compromised in oligodendroglial tumors harboring CIC mutations.…”

Minibrain and Wings apart control organ growth and tissue patterning through down-regulation of Capicua

“…In Drosophila, Cic controls anteroposterior and dorsoventral embryonic polarity, the subdivision of the lateral ectoderm, and pattern formation in several tissues (1,(3)(4)(5)(6). In addition, Cic negatively regulates the growth of imaginal discs and the midgut (7,8). In humans, a single Cic ortholog (CIC) has been implicated in the neurodegenerative disease spinocerebellar ataxia 1 (SCA1) (9), and recently mutations in CIC have been found in the majority of oligodendroglioma cases, suggesting that CIC is a tumor suppressor (10)(11)(12).…”

“…In both Drosophila and mammals, Cic functions as a primary sensor of signaling downstream of the receptor tyrosine kinase (RTK)/extracellular signal-regulated kinase (ERK) pathway (2,(5)(6)(7)(8)(13)(14)(15)(16). According to the current model, activation of RTK signaling results in the accumulation of doubly phosphorylated activated ERK, which directly binds to and phosphorylates Cic (5).…”

La guerre des clones : une compétition cellulaire antitumorale féroce

“…Ils ont constaté qu'en absence de PTP10D, l'expression du facteur de transcription Capicua diminue, ce qui reflète l'activation de la voie EGF [5]. De plus, l'utilisation de deux ARNi différents ciblant, d'une part, PTP10D et, d'autre part, le récepteur à l'EGF (EGFR) rétablit la compétition cellulaire.…”