Cellular Impacts of Striatins and the STRIPAK Complex and Their Roles in the Development and Metastasis in Clinical Cancers (Review)

Abstract

Striatins (STRNs) are generally considered to be cytoplasmic proteins, with lower expression observed in the nucleus and at cell-cell contact regions. Together with protein phosphatase 2A (PP2A), STRNs form the core region of striatin-interacting phosphatase and kinase (STRIPAK) complexes through the coiled-coil region of STRN proteins, which is crucial for substrate recruitment. Over the past two decades, there has been an increasing amount of research into the biological and cellular functions of STRIPAK members. STRNs and the constituent members of the STRIPAK complex have been found to regulate several cellular functions, such as cell cycle control, cell growth, and motility. Dysregulation of these cellular events is associated with cancer development. Importantly, their roles in cancer cells and clinical cancers are becoming recognised, with several STRIPAK components found to have elevated expression in cancerous tissues compared to healthy tissues. These molecules exhibit significant diagnostic and prognostic value across different cancer types and in metastatic progression. The present review comprehensively summarises and discusses the current knowledge of STRNs and core STRIPAK members, in cancer malignancy, from both cellular and clinical perspectives.

Keywords: Hippo signalling; SG2NA; STRIPAK; STRN3; STRN4; Wnt/β-catenin; apoptosis; autophagy; cancer; cell cycle; cell proliferation; clinical cancer; coiled-coil region; diagnosis; kinases; metastasis; phosphatases; prognosis; signalling; striatin; zinedin.

Figure 1

Schematic diagram illustrating the domain structures and chromosome locations of striatin–1 (STRN1), striatin–3 (STRN3) and striatin–4 (STRN4). The structure of each STRN includes four well-recognised domains: the caveolin-binding domain (CaV), the coiled-coil region, the calmodulin-binding domain (CaM) and the WD-repeats domain. The length of the amino acid (aa) sequence is indicated in brackets and the location of corresponding chromosome location is indicated. The arrows in the figure are to indicate location of each domain. Figure created using BioRender.com (agreement number EV266PPC09).

Figure 2

Physical interactions between a constituent member of the striatin-interacting phosphatase and the kinase (STRIPAK) complex. Dimerisation of striatin (STRN) monomers via the coiled-coil region is crucial for substrate recruiting and subcellular targeting. The α-helical chains at the coiled-coil region wind around to form asymmetric homodimers with one chain exhibiting a bend. PP2A (protein phosphatase 2A) interacts with the STRIPAK complex via the coiled-coil region of STRNs. Striatin-interacting molecules STRIP1 and STRIP2 interact directly with the coiled-coil region of STRNs and form mutually exclusive complexes with SIKE1 (suppressor of IKK epsilon-1) and SLMAP (Sarcolemmal membrane-associated protein), or with CTTNBP2/NL (Cortactin binding protein 2 N-terminal like). SIKE1 and CTTNBPs interact with the STRIPAK complex via both the coiled-coil region of STRNs and STRIP1/2. The two MOB4 (monopolar spindle one binder family member 4) at coiled-coil and WD-repeats regions interact with each other in a 3D manner, further bringing PP2A and GCKIII (germinal centre kinase III) members into proximity. CCM3 (Cerebral Cavernous Malformations 3; or PDCD10/TFAR15) also interacts with the STRNs and bridges the interaction between GCKIII and STRN. CaV (Caveolin) and CaM (calmodulin) are known to interact via their respective domains.

Figure 3

Mechanisms of STRIPAK involvement in different signalling pathways. The lines arise from the STRIPAK members and lead to Hippo (black dotted pathway 1–4), Wnt (green dotted pathway 5), Ras (red dotted pathway 6–9), JNK (purple dotted pathway 10–13), p38/MAPK (blue dotted pathway 14), PI3K/AKT (blue-green dotted pathway 15–16) and NF-κB (pink dotted pathway 17) signalling pathways. The potential implications of STRIPAK complex-induced signalling cascade alterations for changing cell behaviour are also listed next to the corresponding signalling cascade. Details of each modulation pathway are described in the main text. A yellow circle filled with black indicates the convergence of two pathway lines. Figure created using BioRender.com (agreement number KW267CSUF2). YAP—Yes-associated protein 1; TAZ—WW-domain-containing transcription regulator 1; TEAD—transcriptional enhanced associated domain; TCF/LEF—T-cell factor/lymphoid enhancer factor; P—Phosphate; GSK3—glycogen synthase kinase 3; CK1—casein kinase 1; APC—adenomatous polysis coli).