Oncogenic KRAS mutations are highly prevalent in colorectal cancer, and a new study reports that phosphorylation of KRAS at serine 181 modulates the invasive and metastatic capacity of colorectal cancer cells. A study published in Cancer Cell International reports that phosphorylation of KRAS at the amino acid serine 181 modulates the invasive and metastatic behavior of colorectal cancer cells. The study indicates that this post-translational modification regulates the invasive and metastatic potential of colorectal cancer cells by controlling the secretion of lysosomal proteins, particularly cathepsin B.
The research team, which included Jesús Daniel Gómez-Zepeda, Montserrat Jaumot and Neus Agell among its authors, used CRISPR-edited SW480 colorectal cancer cells expressing either the phosphorylatable (S181) or non-phosphorylatable (S181A) forms of oncogenic KRAS. One line carried the phosphorylatable form of oncogenic KRAS, in which serine 181 remains available for modification. The other carried a point mutation, designated S181A, that replaces serine with alanine, rendering the protein non-phosphorylatable at that position. Using these CRISPR-edited SW480 cells, the researchers demonstrated that this post-translational modification modulates the invasive and metastatic capacity of the cells.
When the researchers compared the two cell populations, cells expressing the phosphorylatable S181 form of KRAS displayed greater invasive and metastatic potential than their S181A counterparts. In this experimental system, phosphorylation at a single residue within the KRAS protein modulated the invasive and metastatic capacity of the colorectal cancer cells.
To uncover the mechanism behind this behavioral difference, the team turned to secretome analysis, a technique that catalogues the proteins a cell releases into its extracellular environment. The comparison identified 290 proteins whose secretion levels differed between the two cell types. Among these, a pattern emerged: proteins normally resident in lysosomes—the membrane-bound compartments that house the cell’s digestive enzymes—were secreted at reduced levels in the S181A cells. Secretion of lysosomal proteins was specifically reduced in S181A cells, indicating that KRAS phosphorylation exerts a targeted effect on the release of this particular protein class.
Within the lysosomal group, one enzyme stood out. Cathepsin B, a protease associated with cancer invasiveness, was the most abundantly secreted lysosomal protein in cells carrying the phosphorylatable KRAS. In the non-phosphorylatable S181A cells, its release dropped. The enzyme’s intracellular levels, however, were not significantly affected between the two lines, nor was the total lysosome content within the cells. This dissociation between intracellular abundance and extracellular release pinpointed secretion itself—not synthesis, not lysosomal biogenesis—as the step regulated by KRAS phosphorylation.
The researchers then probed the signaling pathways upstream of this secretory event. Protein kinase C (PKC) activity modulated cathepsin B secretion in S181 cells but had a diminished effect in S181A cells. When the team modulated PKC activity in the phosphorylatable cells, cathepsin B secretion responded accordingly. In the S181A cells, by contrast, PKC manipulation had a diminished effect on the enzyme’s release. This difference in PKC responsiveness between the two cell lines suggested that KRAS phosphorylation at Ser181 is involved in the regulation of cathepsin B secretion by PKC.
A second signaling node also proved relevant. The study found that cathepsin B secretion was dependent on PI3K activity, which was lower in S181A cells. The study found that cathepsin B secretion depended on PI3K activity, but that PI3K activity was lower in the S181A cells. This observation suggested a mechanistic chain: phosphorylation of KRAS by PKC facilitates cathepsin B secretion via PI3K activation.
The collective picture is one in which phosphorylation of KRAS at Ser181 regulates the secretion of lysosomal proteins, particularly cathepsin B, in colorectal cancer cells. Intracellular levels of cathepsin B and lysosomes were not significantly affected between the two cell lines, indicating that secretion is the step regulated by KRAS phosphorylation. The authors conclude that this post-translational modification regulates the invasive and metastatic potential of colorectal cancer cells by controlling the secretion of lysosomal proteins, with cathepsin B as the principal cargo.
The authors conclude that KRAS phosphorylation by PKC regulates the invasive and metastatic potential of colorectal cancer cells by controlling secretion of lysosomal proteins, particularly cathepsin B. The study also found that cathepsin B secretion was dependent on PI3K activity, which was lower in S181A cells, suggesting that KRAS phosphorylation facilitates cathepsin B secretion via PI3K activation. The study relied on CRISPR-edited SW480 colorectal cancer cells expressing either the phosphorylatable or non-phosphorylatable forms of oncogenic KRAS. By identifying secretion as the regulated step and cathepsin B as a prominently secreted lysosomal protein, the research links KRAS phosphorylation at Ser181 to the invasive and metastatic capacity of colorectal cancer cells in this experimental system.
Subject of Research: How KRAS phosphorylation at Ser181 regulates cathepsin B secretion and invasive behavior in colorectal cancer cells.
Article Title: KRAS phosphorylation at Ser181 promotes colorectal cancer invasion via regulation of cathepsin B secretion
Article References: Gómez-Zepeda, J. D., Brun, S., Fernandez-Nogueira, M., Blanco-Vargas, S., Ginesta, M. M., Bernaus-Esqué, M., Rentero, C., Estanyol, J. M., Capellà , G., Lu, A., Jaumot, M., & Agell, N. (2026). KRAS phosphorylation at Ser181 promotes colorectal cancer invasion via regulation of cathepsin B secretion. Cancer Cell International. https://doi.org/10.1186/s12935-026-04497-8
Image Credits: AI Generated
DOI: 10.1186/s12935-026-04497-8
Keywords: KRAS, colorectal cancer, cathepsin B, Ser181 phosphorylation, protein kinase C, PI3K, secretome, lysosomal proteins, CRISPR, metastasis, SW480, post-translational modification
News Source: Nathaniel Bowman. (November 6, 2026). KRAS Phosphorylation Drives Colorectal Cancer Invasion by Boosting Cathepsin B Secretion. Scienmag.
