<jats:title>Abstract</jats:title><jats:p>Cell adhesion molecule‐1 (<jats:styled-content style="fixed-case">CADM</jats:styled-content>1) is a member of the immunoglobulin superfamily that functions as a tumor suppressor of lung tumors. We herein demonstrated that <jats:styled-content style="fixed-case">CADM</jats:styled-content>1 interacts with Hippo pathway core kinases and enhances the phosphorylation of <jats:styled-content style="fixed-case">YAP</jats:styled-content>1, and also that the membranous co–expression of <jats:styled-content style="fixed-case">CADM</jats:styled-content>1 and <jats:styled-content style="fixed-case">LATS</jats:styled-content>2 predicts a favorable prognosis in lung adenocarcinoma. <jats:styled-content style="fixed-case">CADM</jats:styled-content>1 significantly repressed the saturation density elevated by <jats:styled-content style="fixed-case">YAP</jats:styled-content>1 overexpression in <jats:styled-content style="fixed-case">NIH</jats:styled-content>3T3 cells. <jats:styled-content style="fixed-case">CADM</jats:styled-content>1 significantly promoted <jats:styled-content style="fixed-case">YAP</jats:styled-content>1 phosphorylation on Ser 127 and downregulated <jats:styled-content style="fixed-case">YAP</jats:styled-content>1 target gene expression at confluency in lung adenocarcinoma cell lines. Moreover, <jats:styled-content style="fixed-case">CADM</jats:styled-content>1 was co–precipitated with multiple Hippo pathway components, including the core kinases <jats:styled-content style="fixed-case">MST</jats:styled-content>1/2 and <jats:styled-content style="fixed-case">LATS</jats:styled-content>1/2, suggesting the involvement of <jats:styled-content style="fixed-case">CADM</jats:styled-content>1 in the regulation of the Hippo pathway through cell‐cell contact. An immunohistochemical analysis of primary lung adenocarcinomas (n = 145) revealed that the histologically low‐grade subtype frequently showed the membranous co–expression of <jats:styled-content style="fixed-case">CADM</jats:styled-content>1 (20/22, 91% of low‐grade; 61/91, 67% of intermediate grade; and 13/32, 41% of high‐grade subtypes; <jats:italic>P</jats:italic> < 0.0001) and <jats:styled-content style="fixed-case">LATS</jats:styled-content>2 (22/22, 100% of low‐grade; 44/91, 48% of intermediate‐grade; and 1/32, 3% of high‐grade subtypes; <jats:italic>P </jats:italic>< 0.0001). A subset analysis of disease‐free survival revealed that the membranous co–expression of <jats:styled-content style="fixed-case">CADM</jats:styled-content>1 and <jats:styled-content style="fixed-case">LATS</jats:styled-content>2 was a favorable prognosis factor (5‐year disease‐free survival rate: 83.8%), even with nuclear <jats:styled-content style="fixed-case">YAP</jats:styled-content>1‐positive expression (5‐year disease‐free survival rate: 83.7%), whereas nuclear <jats:styled-content style="fixed-case">YAP</jats:styled-content>1‐positive cases with the negative expression of <jats:styled-content style="fixed-case">CADM</jats:styled-content>1 and <jats:styled-content style="fixed-case">LATS</jats:styled-content>2 had a poorer prognosis (5‐year disease‐free survival rate: 33.3%). These results indicate that the relationship between <jats:styled-content style="fixed-case">CADM</jats:styled-content>1 and Hippo pathway core kinases at the cell membrane is important for suppressing the oncogenic role of <jats:styled-content style="fixed-case">YAP</jats:styled-content>1.</jats:p>