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Review
. 2017 Jan 25;15(1):7.
doi: 10.1186/s12964-016-0161-y.

The Id-protein family in developmental and cancer-associated pathways

Cornelia Roschger  1 , Chiara Cabrele  2
Affiliations
Review

The Id-protein family in developmental and cancer-associated pathways

Cornelia Roschger et al. Cell Commun Signal. .

Abstract

Inhibitors of DNA binding and cell differentiation (Id) proteins are members of the large family of the helix-loop-helix (HLH) transcription factors, but they lack any DNA-binding motif. During development, the Id proteins play a key role in the regulation of cell-cycle progression and cell differentiation by modulating different cell-cycle regulators both by direct and indirect mechanisms. Several Id-protein interacting partners have been identified thus far, which belong to structurally and functionally unrelated families, including, among others, the class I and II bHLH transcription factors, the retinoblastoma protein and related pocket proteins, the paired-box transcription factors, and the S5a subunit of the 26 S proteasome. Although the HLH domain of the Id proteins is involved in most of their protein-protein interaction events, additional motifs located in their N-terminal and C-terminal regions are required for the recognition of diverse protein partners. The ability of the Id proteins to interact with structurally different proteins is likely to arise from their conformational flexibility: indeed, these proteins contain intrinsically disordered regions that, in the case of the HLH region, undergo folding upon self- or heteroassociation. Besides their crucial role for cell-fate determination and cell-cycle progression during development, other important cellular events have been related to the Id-protein expression in a number of pathologies. Dysregulated Id-protein expression has been associated with tumor growth, vascularization, invasiveness, metastasis, chemoresistance and stemness, as well as with various developmental defects and diseases. Herein we provide an overview on the structural properties, mode of action, biological function and therapeutic potential of these regulatory proteins.

Keywords: Cancer stemness; Cell differentiation; Cell-cycle regulation; Chemoresistance; Development; Helix-loop-helix protein; Id protein; Intrinsically disordered protein.

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Figures

Fig. 1
Fig. 1
Control of DNA transcription by positive and negative HLH regulators. a Broadly expressed bHLH E proteins build heterodimers with tissue-specific bHLH proteins, which results in DNA binding at specific DNA sequences (in red) and DNA-transcription activation. b E-protein association with the Id proteins results in dimers with no ability to bind the DNA because the Id-protein subunit lacks the DNA binding region, which leads to inhibition of DNA-transcription activation. The helices of the HLH domains are represented by cylinders (grey for class I bHLH, orange for class II bHLH and magenta for Id); a blue-colored cylinder represents the basic DNA-binding region of the bHLH domain
Fig. 2
Fig. 2
Amino-acid sequences of the N-terminal (a) and C-terminal domains (b) as well as of the HLH domains (c) of the human Id proteins (for Id1 and Id3 the C-terminus found in a spliced form is reported as Id1′ and Id3L). d Structures of the homodimers of the fragments Id2 30–82 [55] and Id3 29–83 [56]. D-box, destruction box; NES, nuclear export signal (UniProtKB: P41134-1 for Id1, P41134-2 for Id1′, Q02363 for Id2, Q02535 for Id3, P47928 for Id4. GenPept: S71405 GI: 2135331 for Id3L)
Fig. 3
Fig. 3
Selected molecules/pathways involved in the regulation of Id gene expression in normal development and cancer
Fig. 4
Fig. 4
Phosphorylation of Id2 and Id3. These proteins are phosphorylated by Cdk2 at the G1-S transition [–, –123] (a). Phosphorylated Id2 (or its S5D mimic) accumulates in the nucleus, whereas phosphoablated Id2 (S5A) accumulates in the cytoplasm and induces cell-cycle arrest or apoptosis [121, 122] (b). Phosphorylated Id3 induces cell-cycle progression of VSMCs via inhibiting the cell-cycle blocker p21Cip1 at the transcriptional level [123] (c). Phosphorylated Id2 is less resistant to degradation than unphosphorylated Id2. In glioblastoma high Id2 levels can be maintained by PP2A activity (d) [124]
Fig. 5
Fig. 5
The Id proteins promote cell-cycle progression. Cyclin/Cdk-mediated cell-cycle progression is supported by the Id-protein-induced inactivation of the Cdk inhibitors p15/16/21 and Ets, or by the direct interaction of Id2 with hypophosphorylated pRb. In addition, a cross talk between Id1 and the p53 pathway involving the cell-cycle blocker p21 and the Id1 transcriptional repressor DEC1 has been proposed. Also, Id1 may activate the MAPK pathway by promoting the phosphorylation of Raf and MEK1/2, which results in the induction of the transcription factor Egr1, a positive regulator of Id1 and Id3 gene expression
Fig. 6
Fig. 6
Upstream and downstream signals of the Id proteins in some cancer types
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