Monteleon Christine L, McNeal Andrew, Duperret Elizabeth K, Oh Seung J, Schapira Emily, Ridky Todd W
Department of Dermatology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
Department of Dermatology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
J Invest Dermatol. 2015 Sep;135(9):2258-2265. doi: 10.1038/jid.2015.140. Epub 2015 Apr 7.
IQ motif-containing GTPase-activating protein (IQGAP) scaffolding proteins regulate many essential cellular processes including growth factor receptor signaling, cytoskeletal rearrangement, adhesion, and proliferation and are highly expressed in many cancers. Using genetically engineered human skin tissue in vivo, we demonstrate that diminished, sub-physiologic expression of IQGAP1 or IQGAP3 is sufficient to maintain normal epidermal homeostasis, whereas significantly higher levels are required to support tumorigenesis. To target this tumor-specific IQGAP requirement in vivo, we engineered epidermal keratinocytes to express individual IQGAP protein domains designed to compete with endogenous IQGAPs for effector protein binding. Expression of the IQGAP1-IQ motif decoy domain in epidermal tissue in vivo inhibits oncogenic Ras-driven mitogen-activated protein kinase signaling and antagonizes tumorigenesis, without disrupting normal epidermal proliferation or differentiation. These findings define essential non-redundant roles for IQGAP1 and IQGAP3 in the epidermis and demonstrate the potential of IQGAP antagonism for cancer therapy.
含IQ模体的GTP酶激活蛋白（IQGAP）支架蛋白调节许多重要的细胞过程，包括生长因子受体信号传导、细胞骨架重排、黏附及增殖，且在许多癌症中高表达。利用体内基因工程改造的人体皮肤组织，我们证明IQGAP1或IQGAP3的低水平、亚生理表达足以维持正常的表皮稳态，而支持肿瘤发生则需要显著更高的水平。为了在体内靶向这种肿瘤特异性的IQGAP需求，我们对表皮角质形成细胞进行工程改造，使其表达单个IQGAP蛋白结构域，这些结构域旨在与内源性IQGAP竞争效应蛋白结合。体内表皮组织中IQGAP1-IQ模体诱饵结构域的表达可抑制致癌Ras驱动的丝裂原活化蛋白激酶信号传导，并拮抗肿瘤发生，而不会破坏正常的表皮增殖或分化。这些发现确定了IQGAP1和IQGAP3在表皮中的重要非冗余作用，并证明了IQGAP拮抗作用在癌症治疗中的潜力。
