A Unique Family of Neuronal Signaling Proteins Implicated in Oncogenesis and Tumor Suppression

Abstract

The neuronal proteins GAP43 (neuromodulin), MARCKS, and BASP1 are highly expressed in the growth cones of nerve cells where they are involved in signal transmission and cytoskeleton organization. Although their primary structures are unrelated, these signaling proteins share several structural properties like fatty acid modification, and the presence of cationic effector domains. GAP43, MARCKS, and BASP1 bind to cell membrane phospholipids, a process reversibly regulated by protein kinase C-phosphorylation or by binding to the calcium sensor calmodulin (CaM). GAP43, MARCKS, and BASP1 are also expressed in non-neuronal cells, where they may have important functions to manage cytoskeleton architecture, and in case of MARCKS and BASP1 to act as cofactors in transcriptional regulation. During neoplastic cell transformation, the proteins reveal differential expression in normal vs. tumor cells, and display intrinsic tumor promoting or tumor suppressive activities. Whereas GAP43 and MARCKS are oncogenic, tumor suppressive functions have been ascribed to BASP1 and in part to MARCKS depending on the cell type. Like MARCKS, the myristoylated BASP1 protein is localized both in the cytoplasm and in the cell nucleus. Nuclear BASP1 participates in gene regulation converting the Wilms tumor transcription factor WT1 from an oncoprotein into a tumor suppressor. The BASP1 gene is downregulated in many human tumor cell lines particularly in those derived from leukemias, which display elevated levels of WT1 and of the major cancer driver MYC. BASP1 specifically inhibits MYC-induced cell transformation in cultured cells. The tumor suppressive functions of BASP1 and MARCKS could be exploited to expand the spectrum of future innovative therapeutic approaches to inhibit growth and viability of susceptible human tumors.

A Literature-Based Knowledge Graph Embedding Method for Identifying Drug Repurposing Opportunities in Rare Diseases

“…Trifluoperazine is traditionally an antipsychotic but has recently been shown to have anticancer growth properties. 24 In particular, it is believed to inhibit MYC-induced cell transformation. 25 We hypothesize that trifluoperazine’s anti-cancer properties can therefore be used to treat cancers in which MYC is dysregulated, such as Wilms tumors.…”

The brain acid‐soluble protein 1 (BASP1) interferes with the oncogenic capacity of MYC and its binding to calmodulin

“…BASP1 binds to CaM by a small amino-terminal effector domain (ED) (Maekawa et al, 1993;Matsubara et al, 2004;Takasaki et al, 1999) which is a substrate of PKC and N-myristoyl transferase. BASP1 belongs to the GAP43/myristoylated alaninerich C-kinase substrate (MARCKS)/CAP-23 family of myristoylated neuronal growth-associated proteins and shares distinct biochemical properties with the other members MARCKS and growth-associated protein 43 which also bind CaM by their basic EDs (Hartl and Schneider, 2019;Mosevitsky, 2005). Phosphorylation by PKC leads to disruption of the interactions of BASP1 with membrane lipids or CaM (Maekawa et al, 1994;Takasaki et al, 1999).…”

HELZ directly interacts with CCR4–NOT and causes decay of bound mRNAs

“…Interestingly, many of the corresponding proteins have known functions in the biological processes of neurogenesis (25%, q < 5.06 × 10 −12 ) and nervous system development (23%, q < 4.5 × 10 −14 ). These include, for instance, GDNF (glial cell-line–derived neurotrophic factor) family receptor alpha-3 ( GFRA3 ; Baloh et al, 1998; Naveilhan et al, 1998), brain acid soluble protein 1 (BASP1; Hartl & Schneider, 2019), teneurin (TENM1; Tucker, 2018), neurofilament medium polypeptide (NEFM; Coulombe et al, 2001) or the protocadherin G cluster (PCDHG; Keeler et al, 2015), among others (Table S3). After analysis of transcript length and nucleotide composition, we also observed that the mRNAs with increased abundance in the absence of HELZ have longer coding sequences (CDS; P < 2.2 × 10 −16 ) and a higher guanine and cytosine (GC) content across the whole gene ( P = 6.1 × 10 −11 or P < 2.2 × 10 −16 ) compared to all other genes expressed in these cells (down-regulated mRNAs and all mRNAs not significantly altered in Helz -null cells, Fig S5).…”